Eicosanoids and Their Drugs in Cardiovascular Diseases - BPS - Wiley

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke Val´erie Capra,1 Magnus B¨ack,2 Silvia S. Barbieri,3 Marina Camera,1,3 Elena Tremoli,1,3 and G. Enrico Rovati 1 1 Department

of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy of Cardiology and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden 3 Centro Cardiologico Monzino, I.R.C.C.S Milan, Italy

2 Department

Published online 20 March 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21251

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Abstract: Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A2 , are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A2 ) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional  C 2012 Wiley Periodicals, Inc. Med Res Rev, 33, No. 2, 364–438, 2013 antagonists. Key words: eicosanoids; cardiovascular disease; prostanoids; leukotrienes; lipoxins

1. INTRODUCTION A. Biosynthesis of Eicosanoids The term eicosanoid was derived from the Greek word “eicosa” meaning twenty and was introduced in 19791 to describe the compounds derived from carbon-20 unsaturated fatty acids. In humans, the essential fatty acid, arachidonic acid (AA), is a ubiquitous membrane Correspondence to: G. Enrico Rovati, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. E-mail: [email protected] Medicinal Research Reviews, 33, No. 2, 364–438, 2013  C 2012 Wiley Periodicals, Inc.

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Figure 1. Schematic biosynthetic pathways of the eicosanoids produced by arachidonic acid through the intervention of constitutive or inducible enzymes and nonenzymatic pathways that may be relevant to the pathophysiology of cardiovascular system.

constituent that occupies a central role as precursor of a wide variety of mediators produced by the intervention of either constitutive or inducible enzymes, by nonenzymatic pathways, or by transcellular metabolism (Fig. 1). Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators are rapidly generated at sites of inflammation and act through specific receptors that initiate signal transduction events that lead to coordinated cellular responses to specific stimuli.2–6 1. Prostaglandins and Thromboxane A2 Prostanoids, that is, prostaglandins (PGs) PGE2 , PGF2α , PGI2 , PGD2 , and thromboxane A2 (TxA2 ), are the oldest members of the eicosanoid family, first discovered in the early 1930s in seminal fluid from accessorial genital glands; however, the chemical structure of the first two PGs was determined only 30 years later.7 Prostanoids can be biosynthesized from three related fatty acid precursors, 8,11,14-eicosatrienoic acid (homo-γ -linolenic acid), 5,8,11,14eicosatetraenoic acid (AA), and 5,8,11,14,17-eicosapentaenoic acid (EPA or timodonic acid), generating the 1-, 2-, and 3-series PGs, respectively, with the numerals referring to the number of carbon–carbon double bonds present. As in most animals, AA is the most important precursor, and consequently the 2-series PGs are, to a large extent, the most abundant.2 AA is released from cellular phospholipids by cytosolic phospholipase A2 (cPLA2 ),8 and then through the cyclooxygenase and peroxidase activities of the PG endoperoxide (PGH) synthase, commonly called cyclooxygenase (COX), converted into two unstable intermediates, PGG2 and PGH2 (Fig. 2).9 PGH2 , which has a moderately long half-life, is then converted into the biologically active PGs by PG isomerases generating PGE2 , PGD2 , and PGF2α , by prostacyclin synthase to make PGI2 10 or by thromboxane synthase (TXAS) to make TxA2 .11 Two highly related COX enzymes have been identified, COX-1 and COX-2,12 and a number of studies focusing on the expression, distribution, pharmacological inhibition, gene disruption in mice, or overexpression in various cells have addressed the question of their potentially distinct roles. COX-1 is constitutively expressed in most tissues and generates PGs mainly involved in housekeeping functions, such as gastric protection, hemostatic, and renal water balance. COX-2 is highly regulated and Medicinal Research Reviews DOI 10.1002/med

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Figure 2.

The biosynthetic pathways for prostaglandins and thromboxane A2 .

can be induced in response to inflammatory stimuli, even if it can be constitutively expressed in kidney, brain, tracheal epithelium, and some endothelial cells (ECs), and is mainly involved in inflammation, tumorigenesis, and inhibition of platelet aggregation and vasodilation.13

2. Leukotrienes The name leukotrienes (LTs), that is, LTB4 , LTC4 , LTD4, and LTE4 , derive from their discovery in polymorphonuclear leukocytes (PMN) and by the common structure of a conjugated triene.14–16 Their biosynthetic pathway initiates at the nuclear envelope when, subsequent to the action of cPLA2 , AA becomes available for the enzyme 5-lipoxygenase (5-LO),17 which, in association with the 5-LO-activating protein or FLAP,18 catalyzes the formation of 5,6epoxy-7,9–11,14-eicosatetraenoic acid or LTA4 in a two-step reaction with molecular oxygen (Fig. 3).19 LTA4 must then be released by 5-LO and can be further metabolized by either LTA4 hydrolase (LTA4 H)20 or LTC4 synthase (LTC4 S).21 The principal 5-LO products from AA are, in fact, 5-hydroxy-7,9,11,14-eicosatetraenoic acid or LTC4 , essentially a glutathionyl adduct of oxidized AA, and 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid or LTB4 as well as 5S-hydroxy-6-trans,8,11,14-cis-eicosatetraenoic acid (5(S)-HETE). The LTs are formed in many different cells types in response to biological and nonbiological stimuli. Inflammatory cells, such as eosinophils, basophils, mast cells, and alveolar macrophages, can directly synthesize LTC4 ,22 while cells known not to synthesize LTC4 directly, such as platelets and vascular cells, may also be involved in its synthesis via transcellular metabolism (see below). Once formed, LTC4 is transported to the extracellular space where a γ -glutamyltranspeptidase cleaves the glutamic acid moiety to form LTD4 , which by the cleavage of the glycine moiety by a multiplicity of dipeptidases is then transformed into LTE4 . In contrast, the major LT released from neutrophils, monocytes, and macrophages is LTB4 ,15, 23 when LTA4 H stereospecifically adds water to C-12 while retaining specific doublebond geometry. An extensive review of LT synthesis and metabolism can be found elsewhere.19 Medicinal Research Reviews DOI 10.1002/med

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Figure 4.

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The biosynthetic pathways for leukotrienes.

The biosynthetic pathways for lipoxin A4 , 12(S)-HETE, 15(S)-HETE, and resolvin E1.

3. 12- and 15-Hydroxyeicosatetraenoic Acids In addition to 5-LO, AA may also serve as substrate of two other lipoxygenases, namely 12-LO and 15-LO (Fig. 4). In platelets particularly abundant is the 12-LO, which metabolizes AA into 12-hydroperoxyeicosatetraenoic acid (12(S)-HpETE), which in turn is rapidly reduced to 12(S)-HETE.24 On the other hand, two different human 15-LOXs have been identified that differ in tissue distribution and substrate specificity.25 While 15-LOX-1 (leukocyte type) can also metabolize linoleic acid and is mainly expressed in reticulocytes, eosinophils, macrophages, and airway epithelial cells, 15-LOX-2 (epidermis type) preferentially metabolize AA to 15(S)HpETE and successively to 15(S)-HETE, and has a more limited tissue distribution in prostate, lung, and skin. Unfortunately, species–species differences in the product profile formed by the different 12- and 15-LO isoforms make it difficult to directly correlate data obtained in animal models with human diseases.26 In addition, the fact that these enzymes are also involved in the synthesis of anti-inflammatory lipid mediators (LMs—see below and Fig. 4), may partially Medicinal Research Reviews DOI 10.1002/med

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explain the conflicting data on vascular function and on atherosclerosis of these products. A recent review on 12- and 15-LO function and pathological roles can be found elsewhere.27

4. Transcellular Biosynthesis of Eicosanoids The expression transcellular biosynthesis of eicosanoids is used to describe a dynamic condition ultimately resulting in the production of active mediators through cooperation among several cells: a donor cell that transforms AA into an intermediate, and an acceptor cell that accomplishes the biosynthesis into an active mediator. Indication of the existence of transcellular metabolism of prostanoids came from studies in Vane’s laboratory in 197628 and was later corroborated by further studies assessing cell–cell cooperation in vitro. Evidence that a transcellular biosynthetic event can indeed take place in vivo in humans was first obtained in a wound model where TxB2 , 6-keto-PGF1α , and PGE2 were measured in blood before and after treatment with a TXAS inhibitor. The level of the metabolite TxB2 dropped rapidly, whereas there was a significant increase in 6-keto-PGF1α and PGE2 , most likely due to the uptake of platelet-derived PGH2 by ECs and subsequent transcellular biosynthesis of PGI2 and PGE2 .29 The transfer of intermediates was demonstrated to be a common event that can considerably alter the range of active mediators biosynthesized by a tissue in response to a specific stimulus. Evidence have been provided that cells that do not possess the enzymes to produce LTA4 , such as vascular ECs30, 31 and platelets,32 in particular cellular environment, may produce LTC4 from the neutrophil-derived LTA4 .33, 34 For example, adhesion of neutrophils to coronary endothelium creates a favorable setting for the synthesis of cysteinyl-LTs, which, ultimately, may affect organ function35, 36 Another example of this phenomenon is certainly the synthesis of lipoxins (LXs) by the concerted action of more than one LO (see below). An extensive review on transcellular metabolism has been recently published elsewhere.37

5. Lipoxins, Resolvins, and Protectins Besides proinflammatory LMs generated from 5-LO, there are other AA products that are, on the contrary, immunomodulators and function in homeostasis and resolution of inflammation, a process that involves a series of time-orchestrated events. These products are generated by pathways that involve the dual lipoxygenation of AA by either 5- and 12-LO or 15- and 5-LO yielding trihydroxytetraene-containing eicosanoids named LXs, by lipoxygenase interaction products, representing the prototype of transcellular metabolism products (Fig. 4).38, 39 Two main routes of LXs biosynthesis in human cells have been described originating from peripheral blood platelet- or mucosal-PMN interactions.40 In the first case, 15-LO inserts oxygen into AA at the C-15 to produce 15(S)-HETE, which is then rapidly converted by PMN via 5-LO to LXs,38 an event that, besides inducing LX biosynthesis, also reduces LT formation, thus changing the profile of the products generated by activated PMN.41 In the second scenario, the leukocyte 5LO converts AA to LTA4 , which is then released and further transformed by adherent platelets to LXA4 via the LX synthase activity of human 12-LO.42, 43 Another interesting route in the biosynthesis of LXs comes from the intervention of aspirin, a process that generates the so-called aspirin-triggered LXs (ATLs).44 While many of aspirin’s therapeutic benefits can be ascribed to the reduction of platelet aggregation (through irreversible COX inhibition and decreased biosynthesis of TxA2 ), aspirin also initiates the generation of endogenous anti-inflammatory LMs, namely, ATLs. Inflammatory stimuli (e.g., TNFα, LPS, etc.) upregulate COX-2 in vascular ECs or epithelial cells, and when aspirin is administered, COX-2, despite being irreversibly acetylated, remains active but switches its products from precursors for prostanoids, namely PGG2 and PGH2 , to precursor for ATLs, that is, Medicinal Research Reviews DOI 10.1002/med

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The biosynthetic pathways for 20-HETE and EETs.

15(R)-HETE. In activated PMN, this precursor is quickly transformed by 5-LO to 15-epimericLXA4 , or ATL.44 An extensive review of these LMs has been published elsewhere.45, 46 Besides LXs, specialized LMs known as resolvins and protectins were identified,47, 48 which are generated from omega-3 essential polyunsaturated fatty acids, such as EPA and docosahexaenoic acid (DHA), downstream of the 5- and 15-LO in human cells (Fig. 4). They possess potent dual anti-inflammatory and proresolving actions that mediate resolution of inflammation similar to LXs (for a recent review, see Serhan et al.46 ).

6. P450 Epoxygenases Products A third enzymatic pathway of AA metabolism is represented by the P450 (CYP) monooxygenases, of which three isoforms have been shown to be relevant for AA metabolism in human ECs, that is, CYP2C49 and CYP2J50 . These epoxygenases produce four different regio- and stereospecific cis-epoxides, the 14,15-, 11,12-, 8,9-, and 5,6-epoxyeicosatrienoic acids (EETs) (Fig. 5).51 To date no specific EET receptor has been identified, despite specific binding has been obtained in monocytes52 or U937 cells53 and the involvement of a Gs protein has been postulated.54 Alternatively, EETs have been demonstrated to activate transient receptor potential (TRP) channel.55, 56 Indeed, several mechanistic interpretations through which EETs induce smooth muscle hyperpolarization and relaxation have been proposed, all of which seems to converge to an activation of different type of K+ channels.57, 58 More details can be found in a recent review by Campbell et al.59 . In contrast, in kidney,60 liver,61 lung,62 as well as renal,63 cerebral,64 pulmonary,62 and mesenteric65 vasculature, the ω-hydroxylases CYP4A and 4F metabolize AA to 20-HETE (Fig. 5) for which a rather complex mechanism of action has been postulated. This may involve inhibition of the opening of BKCa channels,66 as well as Na+ /K+ -ATPase activity67 and Na+ -K+ -2Cl− transport in the kidney.68, 69 As for the EETs, no specific receptor for 20-HETE has been yet identified, although very recently it has been proposed that 20-HETE-induced constriction of human and rat cerebral arteries is mediated via thromboxane prostanoid (TP) receptors activation70 in line with early reports suggesting the activation of TP receptor following COX-mediated metabolism of 20-HETE into 20-endoperoxides.71, 72 More information on the role of 20-HETE in the cardiovascular (CV) setting can be found elswhere.73 Medicinal Research Reviews DOI 10.1002/med

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7. Isoprostanes Isoprostanes (IsoPs) constitute a complex a family of PG isomers first described as products of non-COX oxidative modifications of AA that results from free-radical attack of cell membrane phospholipids74 or circulating low-density lipoproteins (LDLs).75 After the initial discovery of the F2 -IsoPs,74 it has been observed that other classes of IsoPs are generated from AA yielding the E- and D-IsoPs, isomers to PGE2 and PGD2 , respectively.76 As it will be discussed further, F2 -isoPs have been proved highly useful as biomarkers of lipid peroxidation, an important sign of oxidant stress that is now considered implicated in the etiology of CV as well as other human diseases. However, they must not be regarded as biomarkers only, because the 15-series F2 - and E2 -isoPs also possess pharmacological activity on blood vessels.77 The target of isoPs is a matter of debate.77 While early reports seemed to suggest the presence of a distinct receptor for isoPs in aortic smooth muscle cells (SMCs) and ECs,78, 79 it is now accepted that they are acting through the TP receptor, at least in vivo.80 Indeed, TP receptor blockade produced an additional and more potent anti-inflammatory and anti-atherogenic effect with respect to TxA2 synthesis inhibition in LDL receptor deficient (LDLR−/− ) mice,81 or ameliorates endothelial dysfunction in patients with coronary artery disease (CAD) already treated with aspirin.82 Thus, other agonists different from TxA2 are acting through TP receptor, and isoPs are a very likely candidate.83 Furthermore, there are data suggesting that isoPs may represent another lipid ligand for peroxisome proliferator-activated receptors (PPARs).84 For a recent review see also Milne et al.85

B. Receptors for Eicosanoids Eicosanoids exert their main biological actions activating their cognate G protein-coupled receptors (GPCRs). Nine different prostanoid receptors and six distinct LT receptors have been officially recognized2–4, 6 and classified based on the effects of agonists/antagonists (Table I).86, 87 All these receptors have been classified based upon sequence homology as belonging to Class A rhodopsin-like GPCRs. Phylogenetic investigation indicates that they constitute different clusters with unique molecular signatures in the rhodopsin family, suggesting specific evolutionary origin: (i) prostanoid receptor cluster, including all prostanoid receptors but DP2 ; (ii) chemokine receptor cluster, which includes BLTs, DP2 , and ALX; (iii) purine receptor cluster, counting CysLTs.88–90 In addition, a recent phylogenetic analysis locates OXE close to the purine cluster (Ensembl Genome Browser, entry ENSG00000162881).4 The human TP receptor was the first to be cloned in 1991.91 Since then, most of the human prostanoid receptors were identified by homology screening between 1994 and 1995 (see specific sections below). The first member of the human LT family was cloned after several attempts in 1997 (BLT1 )92 and the last, OXE, in 2002.93 Interestingly, the existence of heterodimers between different receptors of this family and/or expression of distinct receptor isoforms because of splicing events opens up the possibility to multiply the “pharmacological entities” possibly responding to eicosanoids.94–98 Indeed, the existence of others eicosanoid receptors has been suggested over the years by experimental pharmacology.99–101 In this review, only receptors relevant to CV pathophysiology will be considered (Tables II–V). 1. Prostaglandin E2 Receptor, EP Four GPCRs, each encoded by different genes, mediate the actions of PGE2 , confirming functional evidence for receptor subtypes and accounting for several and sometimes divergent effects of PGE2 : EP1 , EP2 , EP3 , and EP4 (Tables I and II). Molecular identification of the human subtypes has been reported and their characterization confirmed they correspond to the Medicinal Research Reviews DOI 10.1002/med

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Table I. Principal Characteristics of Human Receptors for Eicosanoids Officially Recognized by NCIUPHARa

Family

Human gene name

Prostanoidsb Prostanoids

PTGDR GPR44

Gene locus 14q22.1 11q12-q13.3

Receptor acronym DP1 DP2 e

Primary Primary G endogenous protein family ligand(s) transducer Aminoacids

PGD2 11-dehydroTXB2 Prostanoids PTGER1 19p13.1 EP1 PGE2 PGE2 Prostanoids PTGER2 14q22.1 EP2 PGE2 Prostanoids PTGER3 1p31.2 EP3 Prostanoids PTGER4 5p13.1 EP4 PGE2 Prostanoids PTGFR 1p31.1 FP PGF2α Prostanoids PTGIR 19q13.3 IP PGI2 Prostanoids TBXA2R 19p13.3 TP TxA2 Leukotrienesc LTB4R1 14q11.2-q12 BLT1 LTB4 Leukotrienes LTB4R2 14q11.2-q12 BLT2 LTB4 LTD4 Leukotrienes CYSLTR1 Xq13.2–21.1 CysLT1 LTC4 /LTD4 Leukotrienes CYSLTR2 13q14.12-q21.1 CysLT2 Leukotrienes OXER1 2p21 OXE 5-oxo-ETE 19q13.3-q13.4 FPR2/ALX LXA4 Formylpeptided / FPR2 Leukotrienes

Gs Gi

359 395

Gq Gs Gi Gs Gq Gs Gq/G13 Gi/o Gi/o Gq Gq Gi/o Gi

402 358 390f 488 359f 386 343f 352f 389 337 346 423 351

a

NC-IUPHAR-International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (see http://www.iuphar-db.org/index.jsp). b Jones RL, Abramovitz M, Breyer RM, Coleman RA, Hills R, Narumiya S, Woodward DF. Prostanoid receptors. Last modified on 2010–10-22. Accessed on 2011–05-09. IUPHAR database (IUPHARDB), http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=58. c Brink C, Dahlen ´ S-E, Drazen J, Evans JF, Hay DWP, Rovati GE, Serhan CN, Yokomizo T. Leukotriene receptors. Last modified on 2011–02-11. Accessed on 2011–05-09. IUPHAR database (IUPHARDB), http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=35. d Formylpeptide receptors. Last modified on 2010–08-11. Accessed on 2011–05-09. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=23. e Abramovitz M, Breyer RM, Coleman RA, Hills R, Jones RL, Narumiya S, Woodward DF. Prostanoid receptors: DP2 . Last modified on 2010–07-01. Accessed on 2011–05-25. IUPHAR database (IUPHARDB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=339. f mRNA splice variants have been identified for the human EP3 , FP, TP, and BLT1 . The resulting translated proteins differ in the C-tail for prostanoids (see IUPHAR-DB – http://www. iuphar-db.org/index.jsp or Ensembl Genome Browser, entry ENSG00000050628, ENSG00000122420 and ENSG00000006638) and in the N-terminal for the BLT1 (see Section B. 4 for details).

receptors previously defined by pharmacological studies.102 Further heterogeneity arises from the identification of multiple EP3 splice variants in the C-terminal tails that have been identified in human.103 In addition to possessing peculiar biochemical properties, these receptors present distinct signal transduction properties, and cellular/subcellular localization. Despite a foreseen cross-reactivity among these subtypes and isoforms, a number of selective agonists and antagonists have been used to pharmacologically identify subtype expression and function.102 Interestingly, the phylogenetic position of EP receptors in the prostanoid receptor cluster led to suggest that COX pathway system may have been initially composed of PGE2 and its ancestral receptor.88 An extensive review of EP receptor can be found elsewhere.102 Medicinal Research Reviews DOI 10.1002/med

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Table II. Prostanoid Family Receptors in the CV Setting Receptor EP1 EP2 EP3 EP4

IP

TP

CV functions in humans Contraction of pulmonary veins257 Inhibition of platelet function290, 291 Contraction of pulmonary arteries668, 669 Migration of vascular SMCs298 Inhibition of platelet function283, 290, 291, 301, 310 Relaxation of pulmonary veins309 Migration of HUVEC670 Inhibition of platelet function301 Relaxation of pulmonary arteries672 Inhibition of proliferation and migration of vascular SMCs298673–676 Platelet aggregation677 Contraction of pulmonary venous and arterial smooth muscle257, 669 Contraction of vascular SMCs370, 678

Pathological implications Atherosclerosis?289 Cerebral aneurysm293 Atherosclerosis and PAD280, 401 Inflammation306 Abdominal aortic aneurysm671 Pulmonary hypertension395

Stroke391, 392 Atherosclerosis82, 273 PAD390 Hypertension273

2. Prostacyclin Receptor, IP Three different groups cloned the human IP receptor almost simultaneously in 1994.104–106 Activation of IP receptor lead to inhibition of platelet aggregation and to vasodilation.107 Consistent with the most important biological role of PGI2 , IP receptors are widely distributed throughout the body, with predominant CV expression in vascular SMCs and blood platelets (Tables I and II).108 It has also been suggested that the effects of PGI2 on the vasculature are mediated by activation of PPARδ,109, 110 a nuclear receptor whose role in vascular SMC physiology is still rather controversial. Furthermore, a very recent report suggests the existence of a second human receptor for PGI2 , different from the one encoded by PTGIR based on pharmacological and gene silencing data.101 However, this putative receptor has been identified in an airway epithelial cell line and nothing is yet known about its role in the CV system. An extensive review of IP receptor can be found elsewhere.111, 112

3. Thromboxane Prostanoid Receptor, TP Over the years, several pharmacological and biochemical evidences obtained with different ligands, cells or tissues suggested heterogeneity of TP receptors, one in platelets, and one in vessels. In 1991, the TP receptor was cloned from a human placental cDNA library.91 The authors also obtained a partial cDNA clone from the megakaryocyte-like cell line MEG-01, lacking difference in the nucleotide sequences with the placental receptor, and concluded that there was only one TP receptor. Further support came in 1993 when the same lab demonstrated that in humans the TP receptor is generated from a single gene (Table I) spanning over 15 kb containing 3 exons divided by 2 introns, a structure conserved in other prostanoid receptors.108, 113 However, soon after a novel TP receptor was cloned from human ECs114 arising by a novel differential splicing mechanism within exon 3: the potential splice site is utilized resulting in the splicing out of 657 bases (an intron within the TPβ mRNA) comprising the distal portion of the cytoplasmic tail and a portion of the 3 -untranslated region of the TPα mRNA. This mechanism generates two variants that share the first 328 amino acids: the first receptor is termed TPα (343 residues) and is expressed in platelets at high levels; the second, TPβ (407 residues) is primarily Medicinal Research Reviews DOI 10.1002/med

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expressed in ECs. The mRNAs for both splicing variants have been detected in vascular SMCs (Table II).115 The privileged endogenous agonist is TxA2 , although endoperoxide (PGH2 ), other PGs,116 and isoPs80, 117 (see Section A. 7) may act through the interaction with the TP receptor, albeit activating it at higher concentration. For example, Wong et al.118 have demonstrated that COX-2-derived PGF2α acts as an endothelial-derived contracting factor through TP receptor in the hamster aorta. The TP receptor primarily couples to Gq and G13 families of G proteins causing activation of PLC and RhoGEF, respectively, that mainly promotes platelet activation/aggregation and vasoconstriction.117, 119 TP is known to be a typical promiscuous receptor communicating also with Gs and Gi, at least in transfected cells.120 To provide an explanation for the apparent existence of TP subtypes, it was postulated that the selective coupling of splice variants to specific Gα protein can change the affinity of the receptor for agonist ligands.121 Of interest, it has been demonstrated that TP receptor constitutively forms homo- (TPα/TPα) and heterodimers (TPα/TPβ),94 as well as heterodimers with the IP receptor.122 In particular, this latter study shows that TP receptor-induced cAMP generation is augmented upon stimulation with a TP receptor agonist. Furthermore, the interaction between IP and TPα allows mutual regulation of receptor endocytosis through the trafficking pathway determined by the activated dimeric partner.96 This mechanism suggests that the IP receptor might modulate the function of the TP receptor in vivo limiting its cellular effects, something interesting in light of the well-known opposite biological effects that these two systems have in CV physiology123, 124 and pathology.125, 126 Finally, while leaving unaltered the response to traditional TxA2 analogs, the human TPα/TPβ heterodimer has been demonstrated to enhances isoP signaling in HEK293 cells,97 suggesting a potential mechanism for expanding the harmful effects of TP in the CV setting. An extensive review of TP receptors can be found elsewhere.115, 127

4. Leukotriene B4 Receptor, BLT Two receptors for LTB4 have been molecularly identified and termed BLT1 and BLT2 3, 6 forming a gene cluster on human chromosome 14q11.2-q12 with the open reading frame of the BLT2 receptor gene overlapping the promoter region of the BLT1 receptor gene (Table I).128 Both these genes are intronless.3, 6 The BLT1 receptor is primarily, but not exclusively, expressed in leukocytes and represents the high-affinity LTB4 receptor that mediates chemotaxis.92 Two alterative splice variants of the BLT1 receptor have been described in human airway SMCs.98 The resulting translated proteins either lacked the first 100 amino acids or amino acids 43–81 compared with the reference protein. Mutagenesis toward residues within these regions of the BLT1 receptor protein has in other studies shown to alter both ligand binding and signaling capacity.129, 130 The BLT2 receptor is a pharmacologically distinct receptor, which is ubiquitously expressed and displays lower affinity for LTB4 .131–134 Cells transfected with the human BLT1 receptor display a bell-shaped dose dependency for LTB4 -induced chemotaxis with an optimum concentration of 1–10 nM, whereas the corresponding concentration of LTB4 for BLT2 -mediated chemotaxis is higher.92, 131 In addition, while cells expressing a single receptor only respond toward a narrow range of LTB4 concentrations, coxpression of both BLT receptors makes cells migrate toward both very low and high concentrations of LTB4 (1 nM to 10 mM).135 In addition to differential LTB4 affinity, the two BLT receptor subtypes differ in terms of ligand specificity. Although LTB4 appears to be the sole full agonist at the BLT1 receptor,136 platelet-derived 12-LO metabolites 12(S)-HpETE and 12(S)-HETE,136, 137 as well as TXAS metabolite 12Shydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT)138 were recently identified as ligands for Medicinal Research Reviews DOI 10.1002/med

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Table III. Leukotriene Family Receptors in the CV Setting Receptor BLT1

BLT2 CYSLT1

CYSLT2

OXE ALX/FPR2

CV functions in humans Activation of leukocytes, neutrophil, and vascular SM chemotaxis, adhesion of leukocytes to ECs144, 429 Indirect contraction of pulmonary artery679 Integrin-dependent adhesion and MCP-1 production437, 438 Contraction of saphenous veins680 Activation of monocytes/macrophages481, 681, 682 Contractions of atherosclerotic coronary arteries465 Contraction of pulmonary veins683 Expression of P-selectin,487 and de novo synthesis of EGR1, IL-8, and TF488 in ECs Contractions in atherosclerotic coronary arteries465 Modulation of pulmonary veins vascular tone683, 684 Indirect relaxation of pulmonary arteries683 Monocyte chemotaxis and synergism with MCP-1685 Inhibition of chemotactic responses, adhesion, cellular migration, superoxide generation, CD11b/CD18 expression in PMN, inhibition of PMN-epithelial, and EC interactions as well as the activation of monocytes and macrophages46, 348

Pathological implications Atherosclerosis143, 404 Abdominal aortic aneurysm422

Atherosclerosis?409 Atherosclerosis?409, 465

EC inflammation488 Atherosclerosis409, 465

PAD556

the BLT2 receptor. However, the pathophysiological role of BLT2 receptor signaling through these metabolites in the context of CV diseases (CVDs) remains to be established. In addition, intracellular PPARα 139, 140 and the TRPV1 receptor,141, 142 a ligand-gated nonselective cation channel, have been both postulated to be activated by LTB4 . Finally, the expression of BLT subtypes on vascular SMCs and ECs is highly dependent on transcriptional regulation by pro- and anti-inflammatory mediators.143 An extensive review of the BLT receptors can be found elsewhere.144, 145

5. Cysteinyl-LT Receptor, CysLT Two receptors responding to cysteinyl-LTs were cloned in 1999 and 2000 and termed CysLT1 and CysLT2 .3, 6 The recombinant CysLT1 receptor is activated by all the native ligands, with a rank order potency of LTD4 > LTC4 > LTE4 ,146, 147 whereas for CysLT2 receptor the agonist rank order potency is LTD4 = LTC4 with LTE4 being less potent (Tables I and III).148–150 Both receptors mainly couple to Gq, at least in recombinant systems, whereas promiscuous Gq/Gi coupling has been reported in native cells.151 Despite classically the activity of cysteinyl-LTs has been ascribed to the interaction with these two specific plasma membrane receptors, several published data demonstrate that CysLT receptors may localize at nuclear level and crosstalk with other membrane receptors; furthermore, they strongly suggest the existence of additional receptor subtypes and the possibility that CysLT receptors might form homo/heterodimers.99, 152 In this respect, besides GPR17 (see Section H. 3), another purinergic receptor, that is, P2Y12 , has been postulated to be involved in the response induced by LTE4 , though radiolabeled experiments seem to suggest that P2Y12 must complex with another receptor to recognize it.153 Medicinal Research Reviews DOI 10.1002/med

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Finally, the expression of CysLT subtypes on vascular SMCs and ECs is highly dependent on transcriptional regulation by pro- and anti-inflammatory mediators.152 An extensive review of CysLT receptors can be found elsewhere.6, 152 6. Lipoxin Receptor ALX/FPR2 LXA4 and ATLs elicit their cellular responses via a specific GPCR termed ALX/FPR2 (Tables I and III).154 However, ALX/FPR2, besides these LMs, has the ability to interact in vitro with a broad collection of small peptides and proteins that give different signaling responses than either the endogenous ligands LXA4 or ATLs, indicating that ALX/FPR2 can be used in immune responses as a multirecognition target, yet stereoselective.5 Specific LXA4 -binding sites were first characterized on human PMN155 and in promyelocytic (HL-60) cells,156 and demonstrated to induce specific LXA4 responses in these cells. Almost simultaneously, an orphan cDNAs encoding for a GPCR previously cloned from a myeloid cell line was found to display specific [3 H]-LXA4 binding.157 This protein displays high DNA sequence homology to the N-formyl peptide receptor (FPR) (∼70%),158 and, both on the basis of sequence homology, and on the information that the first agonist identified was fMLF,159 this receptor was considered to be similar to FPR, and named FPRL1 (FPR-like 1).160 More recently, an ad hoc IUPHAR commission recognized its ability to bind a number of structurally diverse group of agonists, including N-formyl and nonformyl peptides and LXA4 , just justifying its composite name FPR2/ALX or, ALX/FPR2 when the LX-induced actions or binding is of primary concern.154 Human ALX/FPR2 was subsequently cloned in several types of leukocytes including monocytes and T cells, as well as noncirculating cells such as macrophages, synovial fibroblasts, and intestinal epithelial cells. Ligand-binding experiments have demonstrated that LXA4 also interacts with CysLT1 receptor functioning as a partial agonist to mediate its actions in several tissues and cell types besides leukocytes.157, 161 Therefore, LXA4 interacts with at least two classes of GPCR: one specific for LXA4 , that is present on leukocytes (ALX/FPR2) and the other shared by LTD4 ,162 providing a molecular basis for ATLs serving as an inhibitor of both CysLT1 signals as well as ALX/FPR2-regulated PMN trafficking. Most of ALX/FPR2 effects have been demonstrated to be PTX sensitive, indicating a primary coupling with Gi/o class of G proteins. An extensive review of ALX/FPR2 receptor can be found elsewhere.5, 154

C. Effect of Cardiovascular Risk Factors on Eicosanoid Biosynthesis It is now well established that the majority of CVDs, which include coronary, cerebrovascular, and peripheral arterial disease (PAD), result as complications of atherosclerotic plaque rupture. Indeed, rupture or erosion of vulnerable plaques leads to thrombus formation, which eventually induces vessel occlusion. Atherosclerosis is a chronic disease associated with several pathophysiological reactions within the vascular wall.163, 164 Inflammatory cytokines, oxidized LDLs (ox-LDLs) and changes in shear stress induce first endothelial dysfunction, leading to the increase in the expression of endothelial adhesion molecules and chemokines, with consequent recruitment and activation of circulating leukocytes.165 These events underline the existence of a complex interplay between blood components and cells of the arterial wall. CV risk factors play a fundamental role in the development of this multifactorial pathology and data obtained in large prospective cohort studies, such as the Framingham Heart Study,166 have been particularly useful for designing strategies for treatment and prevention of atherosclerosis. Medicinal Research Reviews DOI 10.1002/med

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CV risk factors are grouped into two broad categories: (i) unmodifiable factors, for example, age (people over the age of 65 represent half of people that have heart attacks), male gender (men have more likely than women to develop CVD, indeed it seems that estrogens have a protective role), heredity and ethnicity; and (ii) modifiable factors, including cigarette smoke, hyperlipidemia, hypertension, diabetes mellitus, physical inactivity, obesity, left ventricular hypertrophy, hyperhomocysteinemia, and thrombogenic factors. 1. Cigarette Smoking The evidence that cigarette smoking increases the risk for CVD is based on several observational studies,167 which show that smoking increases CV mortality by doubling the incidence of CVDs. In particular, evidence from the Framingham Heart Study suggests that the risk of sudden death increases more than tenfold in smoker men and fivefold in smoker women compared to nonsmokers. Cigarette smoking is associated with alteration in the metabolism of eicosanoids with increase in cysteinyl-LTs production and urinary excretion of LTE4 ,168 increase in TxA2 synthesis,169, 170 with no change or slight inhibition in the urinary excretion of stable prostacyclin metabolites.170, 171 A strong relationship between the number of cigarettes smoked/day and the levels of F2 -isoPs in urine has also been observed, which was rapidly modulated by smoking cessation and restarting.172, 173 2. Low-Density Lipoproteins, Triglycerides, and Lipoprotein(a) Elevated serum levels of LDL, cholesterol, and triglycerides together with low levels of highdensity lipoprotein (HDL) cholesterol are strong predictors of CVDs.174, 175 In addition to a direct atherogenic effect,176 very low-density lipoprotein (VLDL) and LDL profoundly affect the coagulation/thrombotic pathways, because they increase the levels in plasma of fibrinogen, factors VII, VIII, and X and plasminogen activator inhibitor type 1 (PAI-1), and they reduce the levels of tissue plasminogen activator (tPA) as well.177 These lipoproteins influence the production of PGs by cells of the arterial wall and by circulating cells, such as platelets and leukocytes. Moreover, oxidative modifications of LDL, a process involving isoP generation, severely influence arterial wall trapping, foam cell formation, and biosynthesis of eicosanoids.178 Lipoprotein(a) [Lp(a)], a LDL-like particle in which an apolipoprotein(a) is linked via a disulfide bond to apoB-100,179 has also been proposed as risk factor for CVDs. This lipoprotein has been shown to have prothrombotic effects and to deliver cholesterol to the sites of vascular injury. Interestingly, Lp(a) has structural homology to plasminogen180 and it induces the production of PAI-1.181 A recently published meta-analysis of 31 prospective studies shows a direct relationship between Lp(a) and CVDs, further supporting the role of this atherogenic lipoprotein as a risk factor for CVDs.182 Unfortunately, the fact that Lp(a) occurs in nature under different isoforms, together with the relatively limited pharmacological approaches capable to modulate its levels, render this biomarker of little value in the medical practice. Higher production of AA metabolites has been reported in hypercholesterolemic patients in association with increased activity of platelet PLAs. In particular, activated platelets from these patients produce greater amounts of TxA2 , as demonstrated by increased levels of 11dehydro-TxB2 in the urine that have been related to their total plasma cholesterol content.183, 184 In addition, these patients showed increased eicosanoid biosynthesis in vivo as indicated by the relatively high levels of 8-iso-PGF2α in urine in comparison with normocholesterol patients.185 3. Hypertension Elevated systolic and diastolic arterial pressure are important CV risk factors.186 The association is strongest for stroke, although it is highly significant also for other CVDs. Cerebral Medicinal Research Reviews DOI 10.1002/med

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blood vessels are the main target of the deleterious effects of hypertension on the brain.187 In addition to inducing structural changes in cerebral vessels, hypertension alters cerebrovascular regulatory mechanisms that are critical for the structural and functional integrity of the brain. These alterations compromise cerebrovascular reserves and render the brain more vulnerable to ischemia, setting the stage for devastating diseases, such as stroke and dementia.187 The direct injury occurring at level of vascular endothelium caused by increases in blood pressure, with consequent alteration also in prostanoid production,188 plays a fundamental role in the increased CV risk induced by this risk factor. It is now evident that some prostanoids play a key role as vasoconstrictor agents inducing abnormal endothelial response.189 Indeed, in essential hypertensive patients, but not in healthy subjects, the intraarterial infusion of high dose of indomethacin, a nonselective COX inhibitor, improves vasodilatation induced by muscarinic agonist, with consequent normalization of forearm blood flow.190 In contrast, indomethacin does not restore vasodilatation in response to acetylcholine in secondary forms of hypertension, which suggests that prostanoids are not important in all cases of hypertension.190 In particular, alterations in PGI2 production by vascular endothelium have been reported by some authors and recent evidence suggests that, while PGI2 , nitric oxide and other molecules help to maintain normal blood pressure,191, 192 others eicosanoids, as TxA2 and PGE2 or isoPs contribute to blood pressure increases.193–195 Interestingly, a previously unrecognized permissive role of PGE2 receptor (EP1 ) in the cerebrovascular dysfunction induced by angiotensin II has been recently reported in the experimental animal.193 This was the first observation that EP1 receptors may be involved in the harmful cerebrovascular effects of angiotensin II, potentially indicating new therapeutic approaches to prevent them.

4. Diabetes Mellitus Diabetes has a negative effect on the microvasculature, the larger arteries, the heart, and the kidneys influencing without distinction all components of CV system. Strong epidemiologic and clinical evidence indicates that diabetes mellitus is a major risk factor for CVDs. In patients with Type 1 insulin-dependent diabetes mellitus, the coronary mortality increases about three- to tenfold, while in man and in female patients with Type 2 insulin-dependent diabetes mellitus, the coronary mortality increases 200- and 300-fold, respectively, compared with agematched nondiabetic control subjects.196 Initial studies on the potential preventive effects of tight glycemic control in Type 2 diabetes, provided evidence of a reduced incidence of CVD events following combined hypoglycemic treatments. These data, however, have been strongly challenged by the results of at least three large clinical trials, for example, ADVANCE, VADT, and ACCORD. Specifically, ADVANCE and VADT found no effect of intensive glucose control on major CV events, and the ACCORD study identified an increased risk of death from CV causes and total mortality associated with intensive glucose control. The discrepancy can be reconciled if one takes into account the fact that, at variance from the UKPDS and DDCT studies, the diabetic condition was prominently associated to other CV risk factors, which of course were not specifically addressed in these studies, thus probably contributing to the excess CV events observed.197 Further studies will dissect this problem. As far as the mechanisms involved in the increased risk of CV events, a number of experimental and clinical studies have demonstrated an important role for endothelial dysfunction in the pathogenesis and clinical manifestation of atherosclerosis that has been associated to Type 2 diabetes and insulin resistance.198 Of relevance is the proven relationship between mitochondrial alterations and oxidation pathways and endothelial dysfunction. Medicinal Research Reviews DOI 10.1002/med

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Alterations in the production of arachidonate metabolites, namely thromboxanes and isoPs, have been repeatedly reported in Type 2 diabetes.199 In particular, increased urinary excretion of 8-iso-PGF2α was detected in diabetics. Moreover, the same study showed that intensive glucose lowering reduced both urinary 8-iso-PGF2α and 11-dehydro-TxB2 excretion rates,200 suggesting a link between lipid peroxidation and glycemic control. Reduced sensitivity of platelets to PGI2 ,201, 202 as well as enhanced platelet sensitivity to a variety of aggregating agents, has been described in diabetic patients.203 Nevertheless, it is not clear whether these abnormalities are intrinsic to the platelet or are a consequence of circulating factors that affect platelet function. Metabolic alterations, oxidative stress, and endothelial dysfunction have been proposed to play a pivotal role. 5. Obesity and Overweight Obesity is an independent risk factor for CVDs in adults204 and in children.205, 206 In particular, body mass index (BMI) above the 95th percentile in adolescence is predictor of adult mortality. Obesity is associated with other risk factors for CVDs, including hypertension (NHANES207 and INTERSALT208, 209 ), atherogenic dyslipidemia, glucose intolerance, and Type 2 diabetes.210 The accumulation of fat in the liver promotes insulin resistance and induces development of dyslipidemia with consequent increase in LDL cholesterol concentrations211, 212 and in triglycerides levels,213 and decrease in HDL levels.211, 212 Moreover, fat accumulation in the liver is associated with increased hepatic synthesis of prothrombotic and proinflammatory mediators as PAI-1, fibrinogen, C-reactive protein (CRP), and inflammatory cytokines.214 In metabolic obesity, a biochemical error occurs that leads to overproduction of PGs215 together with a significant association between increasing BMI and systemic oxidant stress.216 In addition, an association between overweight/obesity has been shown to be associated with enhanced oxidant stress and formation of isoPs.217, 218 In a recent study carried out in patients with obstructive sleep apnea, LTE4 urinary levels increased with increasing BMI values.219 In addition, circulating monocytes from obese patients exhibited increased expression levels of LT synthesizing enzymes, suggesting that obesity may prime inflammatory cells to increase LT synthesis.219 6. C-Reactive Protein CRP is a circulating acute-phase reactant.220 Elevated CRP levels predict recurrent adverse cardiac events and increase mortality in patients with ischemic stroke,221, 222 acute coronary syndromes,223, 224 chronic stable angina,225 or PAD.226 Many evidence suggest that CRP may play a key role in the pathogenesis of CVDs. This protein regulates some crucial steps in atherogenesis, promoting LDL cholesterol uptake by macrophages,227 expression of intracellular adhesion molecules by endothelium,228 production of superoxide and peroxynirite from basal released NO, all events that in turn compromise PGI2 synthesis.229 In addition, CRP increases platelet aggregation and generation of TxA2 .230 7. Fibrinogen Fibrinogen, a circulating glycoprotein produced by the liver, plays a crucial role in the hemostasis acting at the final step in the coagulation response to vascular and tissue injury.231 Inflammation and infectious agents increase fibrinogen synthesis.232 Epidemiological data indicate that fibrinogen is an independent risk factor for CVD. In particular, a direct association between fibrinogen and ischemic stroke,232–234 and PAD235, 236 has been documented. Levels of fibrinogen are usually increased in patients with diabetes, hypertension, obesity, sedentary lifestyles, as well in smokers.237, 238 Fibrinogen has several physiological functions, in particular it regulates cell adhesion, chemotaxis, and cell proliferation,239, 240 vasoconstriction at sites of vessel wall Medicinal Research Reviews DOI 10.1002/med

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injury,231 and blood viscosity.241, 242 Indeed, cleavage by thrombin results in fibrin formation, which in turn is the major component of blood clots.231 In addition, fibrinogen contributes to platelet aggregation by binding glycoprotein IIb/IIIa and increases TxA2 release from activated platelets.243 A complex role is played by fibrinogen degradation products and/or by fibrin at the level of the cells of the vessel wall. Indeed, both decreases and increases in prostacyclin production have been reported after incubation of SMCs or ECs with fibrinogen degradation products or fibrin, respectively.244, 245 Finally, PGI2 inhibits the mobilization of specific binding sites for fibrinogen on platelets, an effect that parallels the inhibition of ADP- or thrombin-induced aggregation.246

8. Hyperhomocysteinemia Elevated serum concentrations of homocysteine are associated with increased risk of CVDs247 and it has been estimated that the incidence of CVDs increases by a factor of 1.6–1.8 every 5 μmol/L increase in plasma homocysteine.248, 249 Concentrations of homocysteine were highly associated with current smoking and systolic blood pressure.247 Homocysteine primarily induces endothelium dysfunction,250 SMCs proliferation,251 platelet aggregation,252 and it increases the Lp(a) binding to fibrin.253 It has been reported that in patients with homozygous homocystinuria due to cystathionine β-synthase deficiency (CBSD) the urinary excretion of 11-dehydro-TxB2 and of 2,3-dinor-TxB2 , the major enzymatic derivatives of TxA2 , increases in all patients compared to the controls.254 The administration of low-dose aspirin or of the antioxidant drug probucol decreased TxA2 production in CBSD patients, suggesting that oxidized lipoproteins can contribute to AA metabolism in platelets of these patients. In addition, it has been suggested that enhanced peroxidation of AA to form bioactive F2 -isoPs observed in the same patients may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CBSD patients. Interestingly, plasma homocysteine levels directly correlate with urinary isoPs and 11-dehydro-TxB2 excretion.255

2. CYCLOOXYGENASE PRODUCTS AND CARDIOVASCULAR PATHOPHYSIOLOGY As mentioned before, COX forms PGs and TxA2 with diverse and partly opposing effects on inflammation, homeostatic biological functions, central nervous system (CNS) and CV function. This intricate network of LMs is unique because the bioavailability of AA yields multiple bioactive products resulting in an array of events that may synergize or be functionally opposed. To add complexity to this picture, a single prostanoid receptor can be activated by more than one autacoid, although with different potency and selectivity, making dissection of each signaling pathway in vivo a hard and risky task. For example, the vasodilator PGI2 (see below) can cause vasoconstriction through activation of the TP receptor in spontaneously hypertensive stroke-prone rats (SHRSP),256 as well as the PGI2 stable analog iloprost (see Section F. 3) can cause contraction of human pulmonary veins through activation of the IP1 receptor.257 From the CV point of view, the most significant products of COX activity are PGI2 , because it is a potent vasodilator, and an inhibitor of platelet aggregation, leukocyte adhesion, and vascular SMC proliferation,192, 258 and TxA2 , because of its important role in platelet activation and vasoconstriction.115 Despite the recent interest on the modulation of platelet reactivity by PGE2 /EP system, CVD research has largely focused on these PGI2 /TxA2 balance because of their involvement in CV physiology,259 and because their biosynthesis is altered in patients with atherosclerosis.260 Medicinal Research Reviews DOI 10.1002/med

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Table IV. Cardiovascular Effects Arising from Alteration of Prostanoid Family Receptor Genes Receptor knockout mice EP1 EP2

EP3

EP4

IP

TP

Effect of gene alterationa Reduced systolic blood pressure and increased renin-angiotensin activity Salt-sensitive hypertension in response to PGE2 ; Reduced PGE2 -induced vasodepression compared to WT mice; PGE2 -mediated renal vasoconstriction, in contrast to the vasodilation seen in WT mice; Increase in mean arterial pressure, in contrast to a decrease in WT mice; Increased excitotoxicity compared to WT mice subjected to the same permanent focal ischemia. Increased basal renal blood flow, decreased renal vascular resistance, and increased PGE2 -mediated renal vasodilation; Reduction in furosemide-stimulated enhancement of diuresis and electrolyte excretion; Increased bleeding tendency and decreased susceptibility to thromboembolism due to a defective activation of platelets. Reduced PGE2 -induced vasodepression compared to wild-type mice; Approximately 95% of neonatal EP4 receptor knockout mice become pale and lethargic around 24 hr after birth and die within 72 hr following birth. The dead neonates exhibit an open ductus arteriosus, while the surviving knockout mice exhibit a partially closed ductus arteriosus. Increased susceptibility to thrombosis; Increased cardiomyocyte, cardiac hypertrophy, and cardiac fibrosis; Enhanced atherogenesis; Enhancement of injury-induced vascular proliferation and platelet activation; Worsening of cardiac injury upon postischemic reperfusion; Development of more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure, when compared to the WT. Delayed atherogenesis; Increase in bleeding time and impaired platelet aggregation in response to TP receptor agonists; Altered renal vascular tone; Inhibition of cytokine-induced increase in beating rate, as seen in WT mice.

a

From the IUPHAR database (IUPHAR-DB) http://www.iuphar-db.org/index.jsp and specific reviews by Kobayashi and Narumiya686 and Yuhki et al.687

D. Prostacyclin and Thromboxane A2 PGI2 is synthesized primarily by vascular ECs,261 and COX-2 appears to be the predominant source of PGI2 formation by the normal vasculature, possibly due to induction of endothelial expression by physiological rates of shear.262 PGI2 plays an important inhibitory role in local control of vascular tone and platelet aggregation,263 leukocyte adhesion to the endothelium, and vascular SMCs proliferation in plaque264 in a tight and complex interplay with TxA2 .123, 124 Numerous investigations using IP receptor knockout (IP−/− ) mice (Table IV) have shown increased propensity toward thrombosis,265 accelerated atherosclerosis,125 intimal hyperplasia and restenosis,124 as well as reperfusion injury.266 In agreement with early demonstration that IP receptor activity has an atheroprotective effect in premenopausal females,267 it has been observed that a PGI2 stable analog, beraprost, or transfection with the enzyme PGI2 synthase (PGIS) inhibited neointimal formation in animal models of arterial injury.268, 269 In a clinical study, the cAMP stimulation deficient IP receptor variant (R212C) was closely linked to disease severity and adverse CV events in patients with CVDs.270 Furthermore, this variant exerts a Medicinal Research Reviews DOI 10.1002/med

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dominant action on the wild-type IP and TPα through dimerization.271 Such findings may implicate altered IP receptor functionality in numerous CVDs, including stroke, myocardial infarction (MI), and hypertension. On the contrary, TxA2 strongly activates platelets, induces vasoconstriction and SMCs proliferation, and is mainly produced in platelets by COX-1, or synthesized by monocytes and vascular SMCs.272 Intriguingly, a significant increase in TP receptor expression has been reported in both atherosclerotic aorta and coronary arteries from ischemic heart disease patients.273 The opposing biological effects of PGI2 and TxA2 on vascular homeostasis might depend on interactions between ECs, platelets, and PMN. In fact, stimulation of TP receptors on ECs increases the expression of the intercellular adhesion molecule 1,274 known to promote monocyte adhesion and to be associated with atherosclerosis progression,275 and upregulates IL-1β-induced vascular cell adhesion molecule 1 expression in aortic vascular SMCs.276 Thus, TxA2 might be also be implicated in plaque growth as apolipoprotein E deficient (ApoE−/− ) TP deficient (TP−/− ) mice exhibited a significant delay in atherogenesis, whereas ApoE−/− IP−/− mice exhibited a significant acceleration in atherogenesis.125 Of interest, common variation in TXAS and PGIS was associated with increased MI risk in the Atherosclerosis Risk in Communities (ARIC) Study.277 These data indicate that PGI2 modulates platelet–vascular interplay in vivo and limits the response to TxA2 .123, 124 The physiological importance of the TP-mediated signaling pathway has been shown in patients suffering from hemostatic defects when a single amino acid substitution in the first cytoplasmic loop (R60L) of this receptor was identified as the responsible of a dominantly inherited bleeding disorder associated with platelet unresponsiveness to TxA2 .278 Last, but not least, the widely recognized efficacy of aspirin in CVDs substantiates the unique importance of TxA2 and PG endoperoxides in platelet activation/aggregation and thrombosis.279

E. Prostaglandin E2 PGE2 appears to mediate an impressive range of biological processes often with opposing effects such as on SM vascular tone and renal hemodynamics,280, 281 PGE2 has been also claimed to be implicated in pathological processes, such as atherosclerosis, aneurysm, and stroke, just limiting to the CV setting, through activation of different EP receptors. However, while an early report indicated that in ApoE−/− mice thrombosis is facilitated primarily by arterial wall-produced PGE2 through activation of EP3 receptor,282 more recently, it was found that only very low levels of PGE2 were present in human plaques and that plaque-induced platelet aggregation was not inhibited by an EP3 nor augmented by an EP4 receptor antagonist, thus suggesting that PGE2 in human atherosclerotic lesions does not modulate atherothrombosis.283 Inflammatory conditions, hypoxia, shear stress, or mechanical perturbations induce the expression of COX-2 and sometimes microsomal PGES-1 (mPGES-1) in human ECs, vascular SMCs, and fibroblasts of the vascular wall leading to the synthesis or increased production of PGE2 (besides PGI2 ).280 An increased presence of COX-2 and the inducible mPGES-1 has been detected in the vascular wall and in the blood of atherosclerotic patients.284 The CV effect of mPGES-1 deletion has been investigated in animal models. Despite nonsteroidal anti-inflammatory drugs (NSAIDs) elevated blood pressure in humans, contradictory evidence emerged from mPGES-1 deletion in hyperlipidemic mice.285, 286 mPGES-1 deletion in hyperlipidemic mice retards atherogenesis,287 attenuates abdominal aortic aneurysm development,286 and reduces the infarct size and indices of tissue injury in model of transient focal ischemia of rodents288 without predisposing to thrombogenesis (possibly via EP3 ), despite the potential cardioprotective effects of EP2/4 . Medicinal Research Reviews DOI 10.1002/med

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Only limited information is available so far on the pathophysiological role of EP1 receptor. It has been suggested that it might play a role in atherosclerosis289 and be relevant to the pulmonary circulation.257 While at least two reports demonstrate that activation of the EP2 receptor by PGE2 or by a selective agonist (ONO-AE1–259) inhibited U-46619-induced platelet aggregation,290, 291 in primary ECs from human carotid arteries, it has been observed that shear stress induced COX2 and EP2 receptor, which in turn trigger early activation of the characteristic inflammatory circuit of NF-kB and CCL-2.292 These results are consistent with data obtained in human and rodent cerebral aneurysm, and accordingly, pharmacological inhibition of COX-2 or EP2 as well as EP2 knockout dramatically reduced the incidence of aneurysm formation.293 Studies from knockout mice and animal models indicate that the presence of EP2 294, 295 and the knockdown of EP3 296 are beneficial in ischemic stroke in vivo. These observations are in agreement with the results from pharmacological stimulation of EP2 with the selective agonist ONO-AE1–259, which indeed reduces brain damage after ischemic stroke.297 The role of EP3 receptor in CVDs is consistent with its expression in the vascular wall,298 and particularly in platelets.299, 300 Activation of EP3 receptor by low doses of PGE2 or by a selective agonist (sulprostone) has been shown to potentiate platelet aggregation,299, 301 an effect that is lacking in EP3 −/− mice302 or inhibited by specific EP3 receptor antagonists.283, 290, 303 Furthermore, EP3 receptor expression seems to be elevated in human atherosclerotic plaques.289 More complicated is the involvement of the EP4 receptor in atherothrombosis. While there are evidences for its implication in the PGE2 -mediated anti-inflammatory effect304 through inhibition of NF-kB activation,305 opposite data have also been published. Potentiation of the proinflammatory cytokine-related effects can occur via the vascular SMCs-derived PGE2 , which has been demonstrated to increase the functional response of human monocytes via activation of EP4 receptor.306 Furthermore, overexpression of EP4 in atherosclerotic vessels has been associated with plaque destabilization and increase in inflammation. These results have been further corroborated by demonstrating that silencing of EP4 receptor inhibits matrix metalloproteinase (MMP-9) expression,307 while EP4 −/− /LDLR−/− double knockout mice had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions.308 This discrepancies may be, at least partially, explained assuming distinct roles for PGE2 in different phases of atherogenesis, that is, a protective role in the early stages and a proinflammatory role in later stages. In addition, EP4 receptor has been observed to mediate human pulmonary vein relaxation, thus suggesting EP4 to be a potential additional target for the treatment of pulmonary hypertension.309 Inhibition of platelet activation by high doses of PGE2 or selective agonist (ONO-AE1–329) has been ascribed to activation of EP4 receptor,291, 301, 310 while accordingly antagonism of EP4 abolished the inhibitory effect of PGE2 .290 In addition, despite a pronounced interindividual variability in platelet response to PGE2 , when the activating EP3 was inhibited with a specific antagonist, the inhibitory effect of EP4 receptor became evident.290

F. Cyclooxygenase Pathway Modulators and Cardiovascular Safety 1. Cyclooxygenase Inhibitors In the past, inhibition of COX enzyme(s) has been the main strategy to inhibit prostanoid biosynthetic pathway due to availability of a broad array of chemically different inhibitors at basically no cost279 Today, there are two classes of NSAIDs: traditional (pre-1995) NSAIDs (tNSAIDs) and COX-2 inhibitors (COXIBs). tNSAIDs, such as aspirin and indomethacin target both COX-1 and COX-2, whereas COXIBs are COX-2 isoform specific.311 Medicinal Research Reviews DOI 10.1002/med

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Upon discovery of the second COX isoform in the early 1990s,312 the analgesic, antipyretic, and anti-inflammatory effects of tNSAIDs were attributed to COX-2 inhibition, whereas the antithrombotic effects and the unwanted renal and gastrointestinal (GI) side effects to COX1 inhibition. This simple idea anticipated the therapeutic benefits of highly selective COX2 inhibitors in the treatment of arthropathies avoiding the most common complication of tNSAIDs, that is, GI toxicity.311 Thus, in the 1990s, a new class of anti-inflammatory drugs rapidly emerged, and the COXIBs were introduced as a second generation of safer NSAIDs, having the advantage of a better GI side-effect profile.313 A number of large, randomized clinical trials confirmed a GI safety advantage of COXIBs over tNSAIDs,314 and COXIBs became one of the most prescribed drugs worldwide. However, soon thereafter the real picture became more complicated as several data accumulated on the potential CV hazard related to the use of COXIBs, leading to the withdrawal of rofecoxib (Vioxx) by Merck and valdecoxib (Bextra) by Pfizer in 2004.315, 316 The mechanism underlying the thrombotic CV risk of COXIBs is still a matter of debate.317, 318 Early reports showed that both celecoxib and rofecoxib significantly reduced the vascular synthesis of PGI2 , leaving unaltered the TxA2 synthesis.262, 319 This led to hypothesize that the CV risk associated to these drugs is due to the disruption of the dynamic balance between the production of TxA2 and PGI2 , the only prostanoid with a documented ability to limit thrombotic events.320 However, the Therapeutic Arthritis Research and GI Event Trial (TARGET) in 2004 showed no difference in the CV risk between lumiracoxib and naproxen, while patients with ibuprofen had more primary CV events than lumiracoxib.321 In 2006, the Multinational Etoricoxib and Diclofenac Arthritis Long-Term (MEDAL) study compared etoricoxib with diclofenac and found no difference in rates of thrombotic CV events.322 Furthermore, observational studies323–330 or meta-analysis331, 332 suggest that most tNSAIDs, while dose dependently reducing the urinary excretion of both PGI2 and TxA2 metabolites,333 have been shown to possess a CV risk very similar to that of selective COXIBs. Thus, there is a need for further examination of the CV safety of all nonselective NSAIDs, besides COXIBs (see also Flavahan et al.318 and Padol et al.334 ). Indeed, most tNSAIDs, apparently with the only exception of naproxen,329–331, 335, 336 tend to mimic the effects of COXIBs, rather than that of aspirin on CV homeostasis, albeit this may vary among compounds and patients.315 Accordingly, significant variability in the degree of COX-2 inhibition and selectivity has been shown among patients taking COXIBs.337 These observations prompted to investigate whether COX-2 gene polymorphisms might correlate with this variability and with the CV risk associated with the use of these drugs. However, two polymorphisms at the 5 and 3 -untranslated regions of the COX-2 gene, despite having both significant effects on reducing COX-2 expression338, 339 and, thus, should be considered “low risk” haplotype, have not been shown to be correlated with a lower risk of coronary events in patients taking COXIBs.340 In addition, the −765G>C polymorphism has been variably associated with the risk of MI and stroke.341, 342 Furthermore, some studies have suggested that COX inhibitors may have pharmacological mechanisms in addition to their COX activity inhibition.343–345 Finally, COXIBs seem to inhibit the synthesis of the so-called ATLs,346 bioactive LMs involved in the resolution of inflammation, particularly by modulating leukocyte adhesion and inhibiting neutrophil–endothelial interactions,347 suggesting further evidence for important regulatory roles for eicosanoids in CVDs.348 (see Section A. 5) 2. TP Receptor Antagonists Pharmacodynamically, treatment with synthesis inhibitors or receptor antagonists should achieve comparable efficacy. Indeed, the TP receptor might be an alternative neglected Medicinal Research Reviews DOI 10.1002/med

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target in CV therapy and may conceptually grant a spectrum of efficacy even superior to aspirin (see below Cayatte et al.83 and Belhassen et al.82 ). Apart from the consideration of GI safety discussed above for COXIBs, issues such as aspirin resistance or the potential advantage of TP receptor antagonism versus TxA2 synthesis inhibitors should prompt the development of new and more potent TP receptor antagonists. In fact, as with any drug (antithrombotic, lipid lowering, or antihypertensive) used to prevent CVDs, treatment “failure” can occur with aspirin, perhaps not surprisingly, given the multifaceted nature of atherothrombosis. Despite a difference between clinical and laboratory aspirin resistance, due to potential confounding factors, during the past years, aspirin resistance has been reported in patients after stroke, PAD, acute MI, and in patients with stable CAD349 or in patients with polycythemia vera.350 Second, tNSAIDS and COXIBs are, to different extent, inhibitors of all the enzymatic metabolites of the COX pathway, and thus to be considered “non specific” drugs. In addition, the inhibition of this enzyme does not affect the synthesis of isoPs that, known to activate TP in vivo,80 may increase in vascular inflammation and oxidant stress, such as during atherogenesis (see Section 5). These findings lead to the conclusion that platelet COX-1 inhibition may not be enough to completely inhibit TP receptor activation, and may only partially influence the history of atherosclerotic injury. Selectivity offered by receptor antagonism at TP would potentially provide a more efficient control of the “bad” mediator (TxA2 and isoPs), while leaving unaffected the “good” ones. However, despite many TP receptor antagonists having developed since the 1980s such as sulotroban (BM-13177),351 daltroban (BM-13505),352 ONO-11120,353 ICI-192605,354 GR32191,355 ONO NT-126,356 KW-3635,357 SQ-29548,358 ifetroban (BMS-180291),359 I-SAP,360 LCB-2853,361, 362 linotroban (HN-11500),363 Z-335,364, 365 they have polarized considerable poor interest, and their development has been stopped because of their toxicity or modest activity in clinical situations.87, 366 Only ramatroban (Bay-u3405)367 and seratrodast (AA-2414)368 has been used clinically for the treatment of asthma in Japan since the late 1990s. The same is also true for TXAS inhibitors or the dual TP antagonists/TXAS inhibitors developed so far.369 Picotamide370 and ozagrel371 have been used clinically as antithrombotic agent (particularly in diabetic patients372 ) or in the treatment of asthma.373, 374 The latter compound, however, despite inducing a CV safe PGI2 accumulation it also increases PGH2 levels, which, acting as a TP receptor agonist, counteracts the reduction of TP receptor-mediated events. It was in 1997 that Servier published a first report on the synthesis of compound S-18886 (terutroban), described as a specific and competitive TP receptor antagonist.375 However, it was only several years later that Cayatte and colleagues demonstrated that terutroban, but not aspirin, inhibited atherogenesis in apoE-deficient mice,83 or injury-induced vascular proliferation and platelet activation in human TP knockin mice.124 In addition, terutroban was also demonstrated to exert antithrombotic effects in porcine376, 377 or canine378 models of thrombosis, as well as to enhance atherosclerotic lesion stability by attenuating inflammatory processes and to revert advanced atherosclerotic plaques in rabbits.379, 380 Consistently, very recent data in SHRSP support the use of terutroban in the prevention of atherothrombosis and of its cerebrovascular and CV complications with effects similar to those obtained with rosuvastatin, and even superior to those of aspirin.381, 382 However, while TP receptor antagonism with terutroban has been shown to delay atherogenesis in the Apobec1/LDLR double knockout mice, coadministration of a COXIB did not increase the efficacy of TP receptor antagonism, but, on the contrary, led to changes in plaque morphology.383 This finding still remains to be explained, because it was not observed in animals given each drug alone.383 At variance, a more recent report demonstrates that terutroban was able to prevent the negative effects of rofecoxib treatment on cardiac function after ischemia– reperfusion injury in APOE3Leiden mice.384 This result is indicative of a potential benefit in Medicinal Research Reviews DOI 10.1002/med

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administrating a TP receptor antagonist to prevent the CV hazard due to the use of COXIBs, particularly in the presence of an established CV risk. Terutroban has also been reported to reduce the inflammatory response during the enhanced atherogenesis that is associated with diabetes,385 and to be protective in an experimental model of Type 2 diabetes386 or in the double transgenic rat model of hypertension.387 In addition, in a model of diabetic nephropathy resistant to aspirin treatment, terutroban reduced renal oxidant stress and proteinuria,388 demonstrating that TxA2 antagonism is associated to significant renoprotection. In preliminary clinical trials with a limited number of subjects, terutroban has been demonstrated to improve endothelial function in CAD patients treated with aspirin,82 or to improve endothelium-dependent vasodilatation and to inhibit platelet aggregation in high CV risk patients taking 300 mg of aspirin.389 In addition, a very recent randomized, double-blind, placebo-controlled trial with 435 patients demonstrated that terutroban was at least as effective as aspirin in PAD patients390 or even superior to it and similar to clopidogrel + aspirin for secondary prevention of ischemic stroke.391 All in all, these data suggest TP receptor blockade to be at least as effective as aspirin in PAD and stroke, and to show synergism/potentiation with TXA2 synthase inhibition in improving endothelial function in high-risk CV patients. Even more interestingly, the just released results from the Phase III PERFORM clinical trial shows that there is no difference between terutroban and aspirin in the primary composite endpoints (fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other nonhemorrhagic vascular deaths), thus suggesting TP receptor blockade to be as effective as the gold standard aspirin.392 However, the same study also suggests that terutroban might confer advantage compared with low-dose aspirin in specific clinical settings, such as reperfusion injuries, restenosis after carotid stenting, small artery diseases of the brain or early atheroma in high vascular risk patients, and, above all, in patients with a history of multiple ischemic strokes previously treated with aspirin. Surprisingly, terutroban did not show any benefit compared with aspirin in terms of GI bleeding and intolerance.392 The reason for this rather unexpected finding is not readily available. Although Servier decided to stop the development of terutroban and all the trials in progress, this drug could still be superior to aspirin at higher doses and/or in a long-term treatment. Above all the PERFORM results strongly support the notion that blocking the platelet-derived TxA2 represent a valid strategy to achieve cardioprotection. The demonstration by Selg et al.393 that both a tNSAID (e.g., diclofenac) and a highly selective COXIB (e.g., lumiracoxib) possess the previously undescribed pharmacological profile of competitive antagonism at the TP receptor may provide the basis to hypothesize a novel class of safer NSAIDs (third generation) and to plan highly innovative studies of structure-activity relationship, chemical synthesis, and pharmacological investigations.394

3. IP Receptor Agonists A brief mention for PGI2 stable analog is needed. The synthetic stable analogues of PGI2 such as iloprost, beraprost, treprostinil, and cicaprost; the synthetic but unstable analog epoprostenol; and the IP agonist alprostadil (synthetic PGE1 ) have been used for the therapy of pulmonary artery hypertension,395 as well as systemic sclerosis,396 especially when combined with sildenafil (an inhibitor of phosphodiesterase V or bosentan, an antagonist of endothelin ET-1 receptor). However, cutaneous flushing, headache, and above all orthostatic hypotension due to systemic vasodilatation, strongly limit their therapeutic use to day-hospital treatment with continuous intravenous (epoprostenol) or subcutaneous (treprostinil) administration. Alternatively, iloprost can be delivered by suitable nebulisers, while oral tablets of beraprost are not yet approved in United States or Europe.395 Medicinal Research Reviews DOI 10.1002/med

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Of note, a novel TP receptor antagonist and IP receptor agonist (TRA-418) has been shown to inhibit human platelet activation/aggregation and to act in an additive and/or synergistic manner in inhibiting platelet–leukocyte interaction.397, 398 In addition, it has been suggested that some drugs, besides their principal mechanism of action, may also perform as “pleiotropic” releasers of endogenous PGI2 , such as angiotensinconverting enzyme inhibitors, statins, β-adrenoceptor blocking agents, antiplatelet thienopyridines (ticlopidine, clopidogrel), and antidiabetic drugs (e.g., gliclazide, metformin).192 On the contrary, IP receptor antagonists have been developed solely based on the potential role of PGI2 in pain, but their potential CV deleterious effects have prevented any clinical use.87 4. mPGES-1 Inhibitors and EP Receptor Modulators mPGES-1 inhibitors were initially thought to retain most of the efficacy of NSAIDs without CV risk associated to COXIBs; however, we have limited amount of information on the pathophysiological role of this enzyme in the CV setting and contrasting data are emerging on the possible compensatory production of other COX products.399, 400 Recent discovery of the complex role of PGE2 on platelet reactivity has led to the development of selective EP receptor modulators that may provide CV benefit. For example, DG-041, being currently evaluated in clinical trials for the treatment of atherothrombosis, is a selective antagonist at EP3 receptor, which may have the advantage of a reduced bleeding risk.401 Conversely, recent discovery of the inhibitory role of EP4 receptor suggests that targeting this subtype with selective agonists could represent an additional way to decrease platelet activity.290, 291

3. LIPOXYGENASE PRODUCTS AND CARDIOVASCULAR PATHOPHYSIOLOGY It should be noted that the current literature on LTs and the biomedical research in this field largely focused on asthma and allergic disorders, mostly ignoring other diseases that are also based on the presence of an inflammatory process with increased vascular permeability and edema, such as CVDs.152 However, an ever growing number of data suggests a major role for 5-LO-generated products in the pathogenesis and progression of CVDs,402 particularly atherosclerosis, MI, stroke, aortic aneurysms, and intimal hyperplasia, as LTs are now recognized as a crucial component of vascular inflammation.403 As mentioned before, while LTs are mostly generated at the nuclear membrane of inflammatory myeloid cells, they can also be synthesized by other cells relevant to the CV system, such as vascular SMCs, ECs, and platelets.404 These actions by themselves imply the existence of a robust link between the LT pathway and CVDs and could provide a novel interpretation of pathogenetic processes that may result in the future in alternate pharmacological approaches to certain CVDs. A major role for the LT pathway in CVDs was suggested by several studies in humans and animal models (for a recent review, see Poekel et al.405 ). It has, for example, been demonstrated that 5-LO contributes importantly to the atherogenic process in mice,406 initially recognized through a reduced 5-LO expression partly responsible for the resistance to atherosclerosis linked to a locus of chromosome 6 in congenic strain (CON6) of mice.407, 408 In addition, 5-LO has been observed to be increased in human aorta, coronary, and CAD specimens and to be associated to mast cells, macrophages, foam cells, and granulocytes, whereas 5-LO expressing cells are augmented in advanced lesions.409 Indeed, genetic studies in healthy subjects show that a promoter variant of 5-LO is associated with an increase in carotid intima-media thickness (CIMT),410 while particular FLAP haplotypes have been linked to an almost twofold increased Medicinal Research Reviews DOI 10.1002/med

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risk of either MI or stroke.411, 412 However, the functional impact of the latter polymorphism is debated. Stimulated leukocytes derived from male carriers with a prior MI, exhibited increased LTB4 formation,411, 412 whereas healthy subjects did not exhibit any difference in the mean level for LTB4 production between carriers and noncarriers of the FLAP haplotypes.413 In addition, not all subsequent studies replicated the association between polymorphisms within the gene for FLAP and the risk of MI.277, 414, 415 Furthermore, subsequent studies in hyperlipidemic mice also disputed previous conclusions. In one study, either ApoE−/− or LDL receptor deficient (LDLR−/− ) exhibited only a minor effect of 5-LO on the formation of lipid-rich lesions.416 Likewise, a recent quantitative analysis of atherosclerotic lesions in ApoE−/− mice did not detect any dependence of lesion size on presence or absence of a functional 5-LO, disputing a role of the 5-LO pathway in intermediate to advanced atherosclerotic lesion development.417 Nevertheless, pharmacological LT inhibition by the FLAP antagonist MK-886 has been associated with a reduction of murine atherosclerosis in other models.403, 418 Also in the case of aortic aneurysm formation, murine models have provided somewhat contradictory results for the 5-LO/LT pathway, with some data suggesting its involvement,416, 419, 420 and others arguing against it.421 The first evidence for the expression of the LT pathway in human abdominal aortic aneurysms was provided by Houard and co-workers.422 LTB4 was mainly derived from the intraluminal thrombus and was identified as a major neutrophil chemoattractant correlating with the release of several proteases.422 Recently, these findings were extended through the demonstration of an increased LTC4 S expression in aneurysms compared with normal aortic wall, leading to an increased amount of also cysteinyl-LTs.423 Furthermore, exogenous LTD4 increased the release of MMP2 and MMP9, and selective inhibition of the CysLT1 R by montelukast blocked this effect.423 Nevertheless, and as will be discussed below, specific targeting of LTB4 signaling appears to consistently be associated with beneficial effects on experimental atherosclerosis, aneurysm formation, and restenosis. In addition to atherosclerosis and abdominal aneurysms, valvular heart disease has also been associated with an inflammatory response, but has received less attention in terms of eicosanoid signaling. Recently, Nagy and co-workers demonstrated the expression of LT synthesizing enzymes and LT receptors in human stenotic aortic valves.424 Aortic stenosis shares several characteristics with atherosclerotic lesions, such as lipid accumulation, inflammatory infiltration, and extracellular matrix degradation leading to extensive calcification of the valvular leaflets, which eventually causes the aortic valve to narrow.425 Increased cysteinyl-LT production in calcified valves was associated with increased production of reactive oxygen species (ROS), activation of osteogenic pathways, and calcification.424 In addition, the expression levels of 5-LO within the aortic valves were significantly associated with the severity of aortic stenosis, as determined by echocardiography.424 These findings indicate that the therapeutic potential of anti-LT drugs in CVD may go beyond atherosclerosis. Difficulties in the interpretation of the results obtained from experiments with knockout mice might depend upon both complications that can arise in the genetic dissection of polygenic diseases such as atherosclerosis,426 and, of course, from species differences between animals and humans. For example, expression of 5-LO and LTA4 H is increased in patients with recent or ongoing symptoms of plaque instability, but not in plaque tissues from two atherosclerosisprone mouse strains.427 However, despite the fact that animal models potentially carry the risk of compensatory mechanisms due to genetic manipulation of the target gene, they are an invaluable tool to study the effects of modification of key enzymes of the LT cascade in a physiological setting that, obviously, cannot be achieved in humans.

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Table V. Cardiovascular Effects Arising from Alteration of Leukotriene Family Receptor Genes Receptor

Gene alteration

BLT1

Knockout Knockout Knockout Knockin Knockdown Knockout Knockout Knockin Knockin Knockin

BLT2 CysLT1 CysLT2

Effect of gene alteration Decrease leukocyte chemotaxis688, 689 Reduction in plaque formation435, 436 Diminished abdominal aortic aneurysm formation420 Increase reperfusion-initiated PMN trafficking608 Decrease blood vessel formation530 Diminished vascular permeability474 Increase vascular permeability484 Increase vascular permeability482, 483 Diminished systemic pressor response482 Increase left ventricular remodeling, induction of apoptosis and impaired cardiac performance485

G. Leukotriene B4 Within human atherosclerotic lesions, the expression of 5-LO and its downstream enzyme LTA4 H leads to local LTB4 formation,409, 428 and subsequent auto- and paracrine signaling though BLT receptors expressed on inflammatory cells and structural component of the vascular wall.429 Genetic studies addressing specifically the LTB4 pathway in CVD have revealed a haplotype of five single nucleotide polymorphisms (SNPs) within the LTA4 H gene, which confers a modest risk of MI in an Icelandic and three different cohorts from the United States.430 Subsequent studies reported that two of the SNPs of this LTA4 H haplotype individually were related to atherothrombotic cerebral infarction in Japanese individuals with metabolic syndrome,431 whereas another SNP within the LTA4 H gene was not associated with an increased risk of MI in two European case–control studies.432, 433 Spontaneous mutations have also been reported around the BLT1 /BLT2 receptor genes, but given the close proximity of the genes encoding those receptors, the SNPs cannot be ascribed to either of the genes alone.433 A case–control study of ischemic stroke in a cohort from the United Kingdom identified variations within this gene cluster with ischemic cerebrovascular events.433 In the latter study, the strongest association was found in a subgroup presenting with cardioembolic stroke, and the findings were replicated for other BLT receptor SNPs in a German stroke cohort.433 As outlined above, while experimental studies of a targeted 5-LO have generated contradictory results,406, 416, 421 either knockout (Table V) or antagonism of the BLT1 receptor reduces both atherosclerotic lesion size and abdominal aortic aneurysms in hyperlipidemic mice.419, 420, 434–436 In human atherosclerotic lesions, macrophage-rich areas stain positive for both the high- and low-affinity receptors for LTB4 ,429 and the chemoattractant activity induced by LTB4 through BLT1 and BLT2 receptor signaling in monocytes has been implicated in the continued accumulation of macrophages at the initial site of foam cell infiltration.434 In addition to chemotaxis, BLT1 receptor signaling in macrophages also induces integrin-dependent adhesion and monocyte chemotactic protein-1 (MCP-1) production.436–438 Furthermore, LTB4 also induces chemotaxis of T-lymphocytes, which accumulate in the vicinity of 5-LO-positive macrophages, and inhibition of LTB4 formation has been associated with a decreased number of T-lymphocytes in atherosclerotic lesions.403 Interestingly, the leukocyte adhesion and migration induced by LTB4 is significantly enhanced in atherosclerotic mice, as determined by intravital microscopy in postcapillary venules,439 further supporting a key role of LTB4 as an inflammatory recruiter in atherosclerosis. However, LTB4 may not only play a role in the initiation and progression of atherosclerosis, but also in the extracellular matrix breakdown associated with atherosclerotic plaque rupture.404 For example, the constituents of the LT Medicinal Research Reviews DOI 10.1002/med

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pathway are expressed at higher levels in carotid atherosclerotic lesions obtained from patients with recent clinical signs of cerebral ischemia (CI) compared with asymptomatic patients.440 One of the key components in plaque instability and rupture is the degradation of extracellular matrix by specific MMPs.441 Since LTB4 production has been associated with increased levels of MMP proteins and/or activity in atherosclerotic lesions,428, 442 human saliva,443 and abdominal aortic aneurysms,416, 420, 422 LTB4 -stimulated MMP activity could potentially link inflammation to plaque rupture. In contrast to the apparent dominant role of mononuclear leukocytes as both the source and targets for LTB4 in atherosclerosis, a differential LTB4 production and BLT receptor expression have been described across human abdominal aortic aneurysms.422 In the latter pathology, neutrophil granulocytes located within the intraluminal thrombus lining the aneurysmal lesions represent the major source of LTB4 , which, in turn, induce a further recruitment of neutrophils.422 However, in the adventitia of both human and murine aortic abdominal aneurysm, the LTB4 production and BLT receptor expression colocalize mainly with macrophages and T-lymphocytes.416, 422 The latter topological distribution of immune cells has raised the concept of an adventitial shift from innate to adaptive immunity in abdominal aortic aneurysms, in which macrophage-derived LTB4 potentially could participate through a leukocyte crosstalk important for lymphocyte recruitment.403 In addition to its role in immunological reactions of atherosclerosis and aneurysm development, LTB4 also activates BLT1 receptors expressed on the endothelium and smooth muscle of the atherosclerotic vascular wall.429 For example, LTB4 -induced migration and proliferation of vascular SMCs have been associated with a thickening of atherosclerotic arteries435 and the formation of intimal hyperplasia.429 In a rabbit model of percutaneous vascular intervention, an orally administered BLT receptor antagonist prevented the development of lesions within an implanted stent,442 suggesting that targeting LTB4 could be a potential therapeutic strategy in interventional cardiology to prevent in-stent restenosis. In this context, it is interesting to note that polymorphisms within the gene encoding FLAP, a protein necessary for LTB4 formation, may be predictive for in-stent restenosis following coronary angioplasty.444 H. Cysteinyl-Leukotrienes The exclusive pharmacological profile of cysteinyl-LTs is characterized by potent actions of CV relevance, they constrict the microvasculature and regulate blood pressure, enhance permeability of the postcapillary venules, reduce coronary blood flow, and reduce cardiac contractility and output without influencing the heart rate.445–449 Furthermore, they can also stimulate proliferation of arterial SMCs and promote P-selectin surface expression, von Willebrand factor secretion, and platelet-activating factor (PAF) synthesis in cultured ECs.152 Recently, it was observed that subjects with high concentrations of cysteinyl-LTs in gingival crevicular fluid have an increased carotid artery wall thickness, regardless of the dental status.443 Coronary artery ligation in rabbit models of MI provides evidence for biosynthesis of cysteinyl-LTs in the heart, in vivo, as 3 hr after ligation a significant elevation of LTE4 in the urine occurs, relative to the sham-operated animals.36 Indeed, cysteinyl-LTs can be produced by coronary arteries450 and levels of cysteinyl-LTs are raised in CAD patients, both before and after coronary artery bypass surgery,451 as well as after episodes of unstable angina.452, 453 As mentioned before, cysteinyl-LTs can be formed from AA by perivascular mast cells, but can also be synthesized by platelets and, probably more importantly, by ECs and vascular SMCs, from neutrophil-derived LTA4 by transcellular metabolism. This process, consequence of leukocyte adhesion, is likely to be accelerated during, for example, ischemia–reperfusion and may lead to a high local availability of cysteinyl-LTs within the ECs, inducing their contraction, thus facilitating emigration of PMNs from the circulating pool.454 A higher PMN count Medicinal Research Reviews DOI 10.1002/med

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and increased urinary excretion of LTE4 have been described after episodes of acute MI and are considered a predisposing factor to MI.452, 455 Accordingly, LTC4 –LTD4 production and coronary spasm in an isolated rabbit heart preparations can be prevented by neutrophil exposure to FLAP inhibitors such as MK 88635 or BAY-X1005456 or to an anti-CD18 antibody,36 leading to a significant cardioprotection and reduced mortality. Similarly, pretreatment of the coronary vessels with first generation cysteinyl-LT receptor antagonists, such as SK104353 or LY171883, protects against coronary constriction and cardiac damage.33, 35 These results are consistent with a local formation of cysteinyl-LTs in the heart via neutrophil-derived LTA4 uptake by endothelial acceptor cells, albeit it is very difficult to perform definitive studies confirming the exact cellular origin of cysteinyl-LTs in CAD. These data may challenge the traditional concept that leukocyte-driven inflammatory response accompanying CV insults is due to the chemotactic metabolite LTB4 , but rather to cysteinyl-LTs. Besides the increase in their level during CVDs, a number of genetic studies also confirm a link between cysteinyl-LTs their receptors and CVDs. The first SNP identified was the LTC4 S −444A>C promoter polymorphism, which has been reported to enhance LTC4 synthesis in eosinophils of patients carrying it.457 This SNP, previously implicated in aspirin intolerant asthma,458 is a controversial one.459 In fact, while in one study coronary artery calcification and CIMT were associated with this LTC4 S promoter polymorphism in women, but not in men,460 in a second report, it was associated with small vessel disease in two different populations showing different magnitudes depending on ischemic stroke subtype.433 At variance, two studies in a Danish population were negative for ischemic stroke in individuals carrying the −444A>C mutation (indeed, in the first study it was even protective), but positive for another polymorphism, that is, the −1072G>A,461, 462 and a two-stage replication design examining polymorphisms in eight genes related to this pathway found little effect on early atherosclerosis and remodeling risk as determined by CIMT.463 Differences in the results of these studies may be due to age differences between the study populations, the risk for initiation versus late stage disease, the role of modifying genes, and ω6/ω3 fatty acid dietary considerations. Very recently, resequencing the gene coding for LTC4 S in an extreme risk population with more than 1500 individuals revealed 17 new mutations, four of which likely change protein function, and were associated with increased risk of venous thromboembolism and ischemic stroke.464

1. CysLT1 : The Controversial Target Both CysLT receptor subtypes are expressed in diseased human arteries.409, 465 However, the role of CysLT1 receptors in CVDs is rather controversial (see also Section K. 1). In monocyte/macrophage such as U937 cells, which exclusively express the CysLT1 receptor, and in primary human monocytes, a number of inflammatory mediators, such as extracellular nucleotides,466 but also fMLP, LTB4 , and PAF, transregulate CysLT1 receptor.467 In this respect, a number of labs have reported a crosstalk/parallelism between CysLT and purinergic receptor systems,151 spacing from dual activation468–470 to receptor cooperation471 or antagonist interactions.472, 473 Thus, the fine tuning of CysLT1 receptor function seems to be important for leukocyte signal processing when multiple mediators are present such as at sites of inflammation, representing an example of feedback mechanism utilized by the cells to protect themselves during pathological processes. A first report on targeted gene disruption reveals the role of CysLT1 R in the enhanced vascular permeability of mice undergoing acute inflammatory responses.474 Furthermore, the multidrug resistance protein-1 (MRP1) inhibitor MK571, or the Cys-LT1 receptor antagonist montelukast reduced vascular ROS production, significantly Medicinal Research Reviews DOI 10.1002/med

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improved EC function, and ameliorated atherosclerotic plaque generation in a mouse model in vivo.475 Of note, assessing relationship between LTC4 biosynthesis with the occurrence of myocardial ischemia per se, or its occurrence during percutaneous coronary interventions, it has been observed recently that the urinary metabolite LTE4 was increased only during acute coronary syndrome and likely during plaque disruption.453 2. CysLT2 : The Promising Target More convincing appear the data regarding the CysLT2 receptor, despite the lack of a selective antagonist, at least until short time ago.476, 477 Kamohara and colleagues478 were the first to report the presence of a functional CysLT2 R on human coronary artery SMCs. They demonstrated that LTC4 enhances [Ca2+ ]i , an effect blocked by the calcium channel blocker nicardipine but not by CysLT1 R antagonists. ECs predominantly express CysLT2 receptor mRNA479–481 and endothelium-targeted expression of the human CysLT2 receptor in mice worsens myocardial ischemia–reperfusion injury by the increase of endothelial permeability,482, 483 while target gene disruption decrease vascular permeability associated with IgE-dependent passive cutaneous anaphylaxis.484 In addition, CysLT2 receptor overexpression induced intensification of inflammatory gene expression, leading to fast left ventricular remodeling, induction of apoptosis in the periinfarct zone, and impairment in the cardiac performance.485 CysLT2 receptor activation in ECs causes a raise in intracellular calcium through the activity of a PTX-insensitive, Gq-protein.486 In addition to direct action on the vascular tone, LT-induced activation of ECs may also lead to changes in the transcriptional activity. In human umbilical vein ECs (HUVECs), LTD4 induces endothelial P-selectin expression,487 strongly stimulates expression of macrophage inflammatory protein-1alpha (MIP-1alpha) in macrophages and MIP-2 in ECs,416 and induced de novo synthesis of early growth response 1 protein, IL-8, and tissue factor (TF),488 Finally, LTD4 and thrombin seem to cooperate in regulating the same genes resulting in a proinflammatory EC phenotype.488 Because LTD4 and thrombin are likely to be formed concomitantly in vivo, CysLT2 receptor and protease-activated receptor-1 may cooperate to augment vascular injury. 3. Cerebral Ischemia: Cysteinyl-LTs, Friend or Foe? CI is clinically characterized by reduced blood circulation, and the resulting hypoperfusion can involve the whole brain, or part of it, thus causing a global or a focal ischemia. It is also characterized by the breakdown of the cerebral blood–brain barrier, and the production of a number of different mediators. Neuronal death during ischemia occurs through a number of identified toxic mechanisms that increase glutamic acid levels, NO biosynthesis, and formation of ROS stimulating development of the inflammatory process and the associated neurotoxicity.489 The general interest in the study of this process is quite recent, though the importance of the inflammatory process that underneath many of the delayed negative clinical manifestations that follow CI has been known since many years.490 The concentration of free AA is usually very low in the brain; however, it has been shown that AA can increase greatly following different stimuli such as ischemia,491 cerebral hemorrhage,492 or traumatic brain injuries,493 and that cPLA2 -deficient mice had smaller infarcts following transient ischemia.494, 495 LTs are synthesized in different areas of the CNS both in vitro and in vivo,496, 497 and in fact, 5-LO is also expressed in the brain,498 despite its functional role in the CNS is poorly understood. The first evidence of neuroprotection, linked to postischemic decrease of LT levels, was obtained in an in vivo model of permanent occlusion of the middle cerebral artery (pMCAo) in the rat by the use of MK-886.499, 500 To corroborate this finding, it has been observed that cysteinylLTs levels were augmented in animal models, particularly after reperfusion,501, 502 and higher Medicinal Research Reviews DOI 10.1002/med

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than normal in cerebrospinal fluid of patients within 72 hr from acute CI.503 Furthermore, as mentioned above, two different variants of the gene that encodes for FLAP have been associated with increased LTs formation together with a doubling of the risk of MI and/or stroke.411, 433 Thus, a number of data indicate that LTs may be involved in mechanisms of increased cell vulnerability in the CNS, despite the similar size of infarct observed in 5-LO−/− and control mice after 60-min transient or permanent oxygen deprivation.504 The vascular formation of cysteinyl-LTs has been observed in the isolated perfused guinea pig brain with an intact and functional vascular endothelial barrier where LTD4 is released into the perfusate following infusion with Granulocyte-macrophage colony-stimulating factor (GM-CSF) primed human neutrophils challenged with fMLP, an observation that is consistent with an underlying mechanism of transcellular biosynthesis.505 Furthermore, in this model, an increase in brain wet weight occurred, suggestive of the formation of an edema that was prevented by pretreatment with the LT synthesis inhibitor MK886, the dual CysLT1 /CysLT2 receptor antagonist Bay u9773 but less by iralukast, a selective CysLT1 receptor antagonist. Expression data suggest that, despite CysLT2 receptor is the main isoform present in the brain, selective CysLT1 receptor antagonists might have protecting effects in CI506–508 possibly decreasing blood–brain barrier permeability.509 Indeed, recently a number of papers have reported the involvement of either CysLT1 510 or CysLT2 511 or both receptors476, 512, 513 in the inflammation process subsequent to a brain vascular insult such as vascular ischemia or oxygen deprivation. Over the years, several groups suggested the existence of more than two CysLTR subtypes in human tissues. This proposal was based on results obtained from functional data where one of the ligand (LTE4 or LTC4 ) failed to elicit or a given antagonist failed to antagonize all cysteinylLT-induced responses.99, 514, 515 Indeed, ligand-binding studies also indicated the existence of a specific LTC4 -binding site in human lung parenchyma516, 517 or in human atherosclerotic coronary arteries465 distinct from that of LTD4 . More recently, new convincing data have been published on the functional recognition of a distinct receptor for cysteinyl-LTs (specific for LTE4 ) in mice lacking the CysLT1 and CysLT2 receptors.518 During the screening for orphan GPCRs at an intermediate phylogenetic position between P2Y and CysLT receptor families, it was found that the heterologous expression of GPR17 in 1321N1 cells results in the generation of an apparently specific and concentration-dependent response to both cysteinyl-LTs and extracellular nucleotides.470 In line with previous expression data,519 human and rat GPR17 are highly present in organs classically undergoing ischemic damage, brain, kidney, and heart. These data are consistent with the demonstration that both the CysLT1 and P2Y12 receptor antagonists (montelukast and cangrelor, respectively) or in vivo GPR17 receptor knockdown protect against brain damage in the pMCAo rat.470 However, it has been shown that GPR17 dimerizes with and is a negative regulator of the CysLT1 receptor, without having a specific response by itself, at least when expressed in a recombinant system.520, 521 This latter observation has been very recently confirmed by another group, supporting the idea that GPR17 alone does not respond to cysteinyl-LTs.522 Thus, whether GPR17 acts as a dualistic receptor or a heterodimer is a matter that deserves further investigation. In both cases, these data increase the complexity of the observed crosstalk between the purinergic and the LT receptor systems.466, 471–473 Data regarding the function of GPR17 in CVD are contradictory. As mentioned above, GPR17 inhibition reduces ischemic damage in the rat,470 whereas it has been observed to orchestrate oligodendrocyte maturation after brain injury at a later stage, suggesting a role in foster brain repair.523–525 However, a different group proposes that GPR17 acts as a negative regulator of oligodendrocyte maturation as its overexpression inhibited terminal differentiation

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of primary precursor cells.526 Thus, whether GPR17 or cysteinyl-LTs are a friend or a foe in ischemic injury still needs to be established.

I. 12S- and 15S-Hydroxyeicosatetraenoic Acids 12(S)-HETE exhibits several CV biological activities, such as vasoconstriction527 and enhancement of angiotensin II-induced signaling.528 In addition, platelet 12(S)-HETE production is increased in SHRSP528 and in subjects with hypertension.529 Furthermore, vascular endothelial growth factor (VEGF) increases the release of 12(S)-HETE, and the VEGF-induced blood vessel formation in vivo and in vitro is inhibited by either the BLT2 R antagonist LY255283 or BLT2 R knockdown by siRNA.530 On the contrary, 12(S)-HETE has also been proposed to be an endothelium-derived hyperpolarizing factor (EDHF) (see below Section L). In addition to direct actions within the vascular wall, 12(S)-HETE signaling has also been reported to be associated with leukocyte and EC activation. For example, 12(S)-HETE induces monocyte adhesion to ECs,531 neutrophil chemotaxis,532 and increased MCP-1 mRNA expression in macrophages.533 These proinflammatory responses induced by 12-LO metabolites from AA are hence in contrast to the anti-inflammatory and proresolution effects of the LXs derived from dual lipoxygenation by 5- and 12-LO (Fig. 4). In human atherosclerotic lesions, the expression of 5-LO and 15-LO-2 has been described in infiltrating macrophages, whereas the levels of 15-LO-1 are undetectable409, 534 A variety of information emerged about the involvement of the 15-LO in atherosclerosis with several contrasting reports.535 For example, it is well known that oxidative modification of cholesterol esters in the LDL particle leads to the formation of atherogenic ox-LDL particles.536 There are a number of data suggesting that 15-LO directly contribute to LDL oxidation and foam cell formation in vitro537, 538 and in vivo.539 Furthermore, 12-/15-LO overexpression in mice induced the recruitment of monocytes into the vessel wall.540 In animal model of atherosclerosis, mice overexpressing the human 15-LO in the endothelium are more susceptible to develop atherosclerotic lesions than littermate controls,541 whereas apo-E542–545 or LDLR546 deficient mice lacking the 12-/15-LO gene were characterized by reduced atherosclerotic lesions. In contrast, there are convincing evidences for an anti-inflammatory and antiatherosclerotic effect of 15-LO generated LMs involved in the resolution of inflammation. The AA metabolite 15-HETE, for example, inhibits superoxide production and degranulation of PMN when stimulated with LTB4 or with PAF547 due to reduction in the affinity of LTB4 receptor for its ligand.548 Accordingly, transgenic rabbits549, 550 overexpressing human 15-LO or mice overexpressing 12-/15-LO551 developed significantly less atherosclerotic lesions. Thus, in light that different species have different 15-LO iso-enzymes with different metabolic profiles, it is still difficult to reconcile these discrepancies and to establish a clear role for this enzyme in atherosclerosis.535 Of notice, while an early report describing a low-affinity receptor for 15-HETE has not been successively confirmed,552 very recently GPR31 has been described as an high-affinity receptor for 12(S)-HETE.553 However, until receptor target(s) will not be firmly identified, which effects are due to a direct activity of this LMs or are dependent by further metabolism to other products (see below), is still a matter of debate.

J. Lipoxins, Resolvins, and Protectins While the role of chronic inflammation in atherogenesis has long been accepted, understanding the pathways of its resolution will offer new approaches to impede atherogenesis.554 In the last years, an increasing numbers of reports indicate that, in addition to functioning as a precursor Medicinal Research Reviews DOI 10.1002/med

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to proinflammatory LMs, that is, LTs, AA is converted to anti-inflammatory LMs, such as the LXs that are produced with a particular time frame during the progression of inflammation. As a result, the integrated response of an individual to a given disease may in part reflect the overall balance of both pro- and anti-inflammatory endogenous systems working in a temporally separated manner.555 As already mentioned, 15- and 5-LO are key LO enzymes in leukocytes and other interacting cells that can synthesize autacoids that can direct tissues toward chronic inflammation or its resolution.15, 38 LX actions include inhibition of chemotactic responses, adhesion, cellular migration, superoxide generation, CD11b/CD18 expression and inositol phosphate 3 formation in PMN, inhibition of PMN-epithelial, and EC interactions as well as the activation of monocytes and macrophages.46, 348 Interestingly, recent data show that patients with PAD have a defect in generation of proresolution LM, 15-epi-LXA4 .556 A particular mention is needed for ATLs. As previously mentioned, when aspirin is administered, COX-2 is irreversibly acetylated and changes its product profile from intermediates for prostanoids to precursors for ATLs.44 Indeed, it has been shown that in a randomized clinical trial carried out in healthy subjects that low-dose aspirin treatment decreases plasma TxB2 , an indicator of platelet reactivity, whereas it increases ATL levels, demonstrating that aspirin initiates the production of anti-inflammatory ATLs opposite to the inhibition of TxA2 .557 Surprisingly, in the absence of aspirin, the HMG-CoA reductase inhibitor atorvastatin, and the antidiabetic PPAR-γ ligand pioglitazone triggered 15-epi-LXA4 generation that is in turn inhibited by selective pharmacological targeting of either COX-2 or 5-LO.558 These results have been also corroborated by showing that another PPAR-γ agonist, rosiglitazone, also increases cerebral LXA4 levels and inhibits the production of LTB4 , thus inducing neuroprotection in the experimental stroke model of pMCAo.559 To explain these findings the authors hypothesize a potential posttranslational modification of COX-2 by S-nitrosylation, a process that seems to be involved in atorvastatin-mediated cardioprotection.560 The enhanced formation of 15-epiLXA4 by statins was recently confirmed in a report demonstrating that lovastatin promotes 15-epi-LXA4 formation that may be relevant in the protection from inflammation in a murine model of airway mucosal injury.561 Interestingly, it has been also shown that both aspirin- and ATLs-induced inhibition of leukocyte trafficking is abolished in NO synthase knockout mice.562 Taken together, these results suggest that aspirin evokes vascular ATLs generation, which in turn stimulates local NO and PGI2 production563 that participates in anti-inflammatory circuits in vivo providing an amplifying mechanism for 15-epi-LXA4 generation.564 However, potential adverse interactions can occur when COX-2 is both acetylated and S-nitrosylated, because activity of COX-2 in promoting 15-epi-LXA4 formation is inhibited.565 Given that many CVD patients assume both antiplatelet and cholesterol-lowering drugs, further studies on the impact of this combination therapy should be conducted.566 Bringing into focus the tightly orchestrated interplay between COX and LO products, this hypothesis integrates the “imbalance theory” on PGI2 /TxA2 production to explain the increased CV risks of COXIBs,320 providing further evidence for important regulatory roles for eicosanoids in CVDs. Two recent studies have addressed the possible proresolving actions of 15-LO downstream products in the inflammation associated with atherosclerosis in human. A first genetic case– control study aimed at characterizing the 15-LO haplotypes in Caucasians, discovered a functional SNP and reported that heterozygotes for a −292C>T variant in the promoter of the 15-LO gene (which was associated with higher enzyme expression in vitro567 ) showed a tendency toward protection against atherosclerosis.568 On the other hand, in another study, Assimes et al. described a coding SNP (T560M) variant in the 15-LO gene that, at variance, is associated with a 20-fold reduction in enzyme activity. Genotyping of atherosclerotic disease in the Coronary Artery Risk Development in Young Adults and in the ARIC study cohorts showed that heterozygote carriers of this near-null 560M allele had an increased risk of clinical CAD.569 Medicinal Research Reviews DOI 10.1002/med

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Thus, the only two available clinical trials support a protective role of 15-LO expression against CAD in humans. Large-scale genetic association studies will be necessary to definitively show whether the anti- or the proatherosclerotic effects of 15-LO predominate in humans.535 Furthermore, as mentioned before, LMs also known as resolvins and protectins (the latters not strictly eicosanoids, as generated from DHA) possess potent dual anti-inflammatory and proresolving actions that mediate resolution of inflammation similarly to LXs.570 However, they seem to exert their effect through a different set of receptors, such as ChemR23 for resolvin E1 (RvE1) and 18S-RvE1 and GPR32 for RvD1.571–573 These new products of the metabolism of the long chain  3 fatty acid DHA are of interest in the context of CVDs considering the body of data available on the cardioprotective effect of the  3 fatty acids, despite a limited information about its mechanism.574–576 For example, RvE1 selectively blocked TP agonist U46619-stimulated,577 and ADP-stimulated platelet aggregation through ChemR23 activation,578, 579 while neuroprotectin D1 eliciting neuroprotection in experimental stroke in rats.580 RvE1 was in addition identified as a BLT1 receptor partial agonist, suggesting that this endogenous anti-inflammatory LM could act through inhibition of LTB4 -induced signaling.581 These data suggest that LXA4 , resolvins, and protectins, are potent proresolving mediators that demonstrate regulation of multiple proinflammatory cytokines, and that a failure of endogenous resolution mechanisms may underlie the continuous inflammation that promote atherosclerosis.

K. Lipoxygenase Pathway Modulators and Cardiovascular Effects 1. Antileukotriene Drugs LT modifiers, that is, synthase inhibitor and CysLT receptor antagonists (LTRAs) have been licensed for a long time for the treatment of asthma and allergic rhinitis, conditions in which inflammation plays an established role (for a review, see Capra et al.582 ). Despite the inflammatory component of CVDs being a well-accepted concept, only recently attention has been paid to the use of LT modifiers in this pathological condition, yet with heterogeneous and controversial results. 5-LO inhibitors and antagonists at the CysLT and BLT receptors have been tested in animal models of experimental MI and CI, atherosclerosis and vascular injury, providing promising results. Indeed, significant reduction of infarct size, inflammation, atherosclerotic lesion size, and intima-media thickness has been observed with inhibition of LT biosynthesis by either selective 5-LO583–585 and FLAP inhibitors,403, 418, 456 or dual LO-COX blocking agents.586, 587 The most encouraging results have been reported with REV-5901, a compound combining activity as 5-LO inhibitor and LTRA.588 Though, in spite of persistent inhibition of zymosan-stimulated LT production in canine blood, a failure in the reduction of the extent of MI size following occlusion-reperfusion has been observed.589 Furthermore, studies using 5-LO-deficient mice did not reveal any difference in infarct area or atherosclerosis between knockout and littermates controls.416, 590 More recently, two 5-LO inhibitors showed opposite effects resulting in lack of efficacy in apoE−/− mice (L739,010),417 but 40% reduction in the CIMT in LDLR−/− mice (ZD4407).591 However, based on the efficacy in animal model of the FLAP-inhibitors, a prospective clinical trial with DG-031 (previously known as BAY-X1005) was conducted in patients carrying the at-risk variants of FLAP and LTA4 H, showing a dose-dependent and significant reduction of biomarkers associated with increased risk of MI.592 Furthermore, in a double-blind Phase II clinical trial versus placebo, reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in patients treated with the new 5-LO inhibitor VIA-2291, proving a first suggestion that a reduction in LT production may influence atherosclerosis in humans.593 Medicinal Research Reviews DOI 10.1002/med

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Pharmacologically specific inhibition of LTB4 signaling can be achieved by means of BLT receptor antagonists, which were initially developed to treat rheumatoid arthritis and COPD. In hypercholesterolemic mice, the selective BLT1 receptor antagonist CP-105,696 reduces both atherosclerotic lesion size434 and abdominal aortic aneurysms.419 Likewise the prodrug BIIL-284, which is metabolized in vivo into a BLT1 /BLT2 receptor antagonist, reduces intimal hyperplasia in different animal models.429, 442 Studies with LTRAs illustrate a controversial situation as results that suggest a role for cysteinyl-LTs in the expansion of ischemic damage and in cardiac dysfunction during reperfusion35, 594, 595 are evenly balanced by others suggesting that they have no or little effect on the progression of myocardial injury.596, 597 These observations could result from a poor activity displayed by some of these compounds on the CysLT2 receptor (unpublished observations), or arise from the use of LTRAs of the first generation that, displaying a insufficient potency, cannot compete with the endogenous ligands likely to be highly concentrated at sites where inflammatory cell accumulate and myocardial injury takes place. In fact, the more recent, potent and commercially available CysLT1 receptor antagonist montelukast has been found to inhibit atherosclerotic lesion size and intimal hyperplasia in mice,598, 599 and to significantly reduce the neointima, decrease macrophage content, increase SMC content, and inhibit expression of MCP-1 without having influence on plasma lipids, in a rabbit carotid balloon injury, indicating antiatherogenic effects unrelated to plasma lipid modulation.600 Recently, it has been shown that montelukast or the MRP1-inhibitor MK571 reduce the levels of oxidant stress and apoptosis and give positive effects on myocardial remodeling after left ventricular injury.601 Interestingly, a randomized controlled trial of placebo versus either montelukast or theophylline in asthmatics, reported significantly lower levels of CRP in montelukast treated patients.602 There is no simple explanation for these apparent contradictory findings. For example, inhibitors of LT synthesis could afford a more effective rescue of ischemic myocardium by preventing formation of vasoactive cysteinyl-LTs and chemotactic LTB4 . Nevertheless, 5-LO inhibition will also inhibit the formation of anti-inflammatory and proresolving LXs. Thus, while most studies targeting 5-LO or FLAP support a role in MI pathogenesis, studies targeting LT receptors provide mixed results. This, as mentioned before, might indicate that additional receptors in addition to those blocked by currently available compounds, are involved in transducing the LT effects.

2. Lipoxin Stable Analogs Being autacoids, both LXA4 and ATL are rapidly produced in response to stimuli, function at a local environment and are inactivated by metabolic enzymes. Therefore, there was a need for stable analogs synthesized based on the native structures of LXA4 and ATLs.603 These compounds are resistant to enzymatic metabolism, while maintaining their structural integrity and exhibiting enhanced bioactivity. For example, 15(R/S)-methyl-LXA4 is a racemic stable analog of both LXA4 and ATLs that is not rapidly metabolized to the 15-oxo-LXA4 , and posses an augmented bioaction in vitro603 and in vivo.604 Additional analogs of LXA4 and ATLs were synthesized adding a phenoxy group and a fluoride to hamper their degradation thus prolonging the half-life and enhancing their potency and bioavailability in vivo.605, 606 For example, stable LX analogs superfused in vivo in the rat mesentery reduce L-NAME-induced leukocyte rolling and adherence by attenuating P-selectin expression.607 In a BLT transgenic mice model, and despite excessive PMN recruitment, intravenous injection of ATLs sharply diminished reperfusion-initiated PMN trafficking to remote organs,608 while modulating expression of adhesion molecules on human leukocytes and neutrophil adhesion to coronary artery ECs in whole blood in vitro.347 Furthermore, different ALX/FPR2 agonists in vivo provide protection against ischemia–reperfusion mediated injury to the myocardium, showing a pivotal Medicinal Research Reviews DOI 10.1002/med

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role for circulating neutrophil in acute ischemic injury. For example, CGEN-855A, a novel 21amino acid peptide agonist, displays anti-inflammatory activity inhibiting PMN recruitment to inflamed air pouch, and providing protection against ischemia–reperfusion injury through inhibition of PMN recruitment to the myocardium.609 Interestingly, the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides has been demonstrated to activate the LXA4 receptor to halt PMN diapedesis,610 thus confirming previous observations on the cardioprotective role of ALX/FPR2 independently of FPR1 receptor activation.611, 612 Finally, it is widely accepted that one of the major features shared by CVDs is the increased production of ROS generated by vascular NAD(P)H oxidase activation and EC proliferation. ATL stable analogs induce heme oxygenase-1 expression, which confers protection against prooxidant insults,613 and suppress NAD(P)H oxidase-mediated ROS generation,614 while inhibit human EC proliferation and migration,615 strongly indicating that LXs may play a protective role against the development and progression of CVDs. As a result, these metabolic stable analogs serve as useful tools both in vitro and in vivo to investigate LXA4 and ATLs action, and can be used as a guide in the development of innovative therapeutic interventions.348

4. EPOXYOXYGENASE PRODUCTS AND CARDIOVASCULAR PATHOPHYSIOLOGY L. EET and 20-HETE While a large number of observations demonstrate that EETs act as EDHF in response to acetylcholine, bradykinin, or shear stress, which other substances induce vascular relaxation is still a matter of debate. For example, some human or animals arteries do not synthesize EETs,616 but other factors have been implicated in endothelium hyperpolarization and vessel relaxation such as K+ ,617 hydrogen peroxide,618 C-type natriuretic peptide,619 or LO metabolites of AA such as the 15-LO-1 metabolite 11,12,15-trihydroxyeicosatrienoic acid or the 12-LO metabolite 12-HETE.620 A number of studies in animal models and in humans reflected this differences. For example, while CYP inhibition in dogs coronary artery inhibit acetylcholine-621, 622 or bradykinin-induced623 vasorelaxation as well as AA-induced dilation,624 in humans contrasting data have been published, some with positive625, 626 and others with negative results.627, 628 A partial explanation to these discrepancies may be attributed to the fact that in many human studies it has been used sulfaphenazole, an inhibitor of CYP2C9, while other isoenzymes might may participate in CYP/EET-mediated responses. Even more controversial appear to be the situation regarding another P450 epoxygenase product, that is, 20-HETE. As mentioned before, at variance with ECs, vascular SMCs mainly synthetize 20-HETE. Apart from its involvement in sodium transport67 and modulation of the natriuretic effects of parathyroid hormone, endothelin, or angiotensin,629–631 20-HETE has a clear role in the control of vascular tone, eliciting vasoconstriction by modulation of K+ channels.632, 633 Very recently elevated levels of 20-HETE have been detected in patients after aneurysmal subarachnoid hemorrhage and statistically associated to delay CI.634 These data in humans seem to confirm a number of early reports demonstrating that the production of 20-HETE is elevated in the cerebral vasculature of SHRSP,635 while its synthesis inhibition opposes cerebral vasospasm and reduces infarct size in ischemic models of stroke.636–641 However, in humans two different polymorfisms have been identified and associated with cerebral infarct,642–644 one of which has been demonstrated to decrease 20-HETE formation and might increase the risk of ischemic stroke.645 Therefore, the real picture is far from clear on whether 20-HETE favors or not stroke. Medicinal Research Reviews DOI 10.1002/med

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M. Epoxyoxygenase Modulators Given the complex vascular and renal effects of 20-HETE discussed above, synthase inhibitors and 20-HETE mimetics have been both proposed in the treatment of hypertension and associated CVDs. However, again, results are divergent depending on the model utilized (for more details, see Kroetz et al.646 ). Among several inhibitors of P450 epoxygenase have been developed to date, TS-011 and HET0016 have been proven beneficial in animal models of CI. TS-011 was shown to decrease infarct volume,636, 640 to ameliorate microcirculation after reperfusion in the penumbra638, 641 and to improve long-term neurological and functional outcomes.639 Similar results were obtained with the most potent inhibitor to date, HET0016, although its use seems to be limited by a short biologic half-life, poor solubility and stability.637, 640 In conclusion, while enhancement of the production of vascular EETs or inhibition of their degradation as well as modulation of 20-HETE production may represent a new therapeutic approach to endothelial dysfunction and CVDs, certainly more studies are needed to clarify a direct cause–effect relationship (see Williams et al.,73 for more details).

5. ISOPROSTANES AND CARDIOVASCULAR PATHOPHYSIOLOGY In the last decade, isoPs have become the “gold standard” biomarker of oxidant stress in vitro and in vivo,647, 648 and they are emerging as potential mediators in vascular pathology because they exert profound vasoconstrictor activity in a variety of vascular beds, including the kidney, lung, heart, and brain.649–652 Consistent with these data, increased levels of isoPs have been demonstrated in atherosclerotic tissue of humans653 and animals,654 as well as in several disorders in which vascular pathology is prominent, such as diabetes,200 reperfusion syndromes,655 and hypercholesterolemia.656 Accordingly, exogenous antioxidants such as vitamin E, reduce both their levels and the development of the disease.657, 658 Urinary and plasma levels of 8-isoPGF2α have been demonstrated to be, respectively, risk marker659 and to be associated with the presence and extent of coronary stenosis in patients with CAD,660 suggesting a correlation between their levels and plaque instability.661 Furthermore, F2 -isoPs induce endothelin release and proliferation of vascular SMCs,662 while there is also additional evidence that this molecule can increase resistance to aspirin inhibition of platelet aggregation,663, 664 despite it has also been reported inhibition of platelet aggregation in whole blood.665 It should be remembered here that 8-iso-PGF2α is a partial agonist of the TP receptor compared to U46619 in the coronary vasculature.666 Typically, the attitude of partial agonists to behave as agonist or antagonist depends on the level of the full agonist (TxA2 in this case) simultaneously present, and this might in part explain these contradictory results. As mentioned above (see Section B. 3), isoP responses are enhanced in cells expressing the TPα/TPβ heterodimer, relative to cells expressing TPα or TPβ individually,97 something that can be related to the development and/or progression of CVDs. Taken together, the fact that isoP plasma levels are elevated in so many major disorders in humans, such as CVDs, make the inhibition of their synthesis or of their target receptor of particular therapeutic interest.667

6. CONCLUSIONS It is clear that the AA cascade is a strong and vibrant research area, and recent discoveries have highlighted the role not only of the COX metabolite prostanoids, but also of LO metabolites, as Medicinal Research Reviews DOI 10.1002/med

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well as of nonenzymatic products, in atherosclerosis, CAD, and stroke. This intricate network of LMs is unique not only because from a single precursor, AA, different enzymes may generate a number of different products with similar or opposite pharmacological profile, but also because differences in spatial and temporal conditions may induce a shift in the end products within LO and between LO and COX pathways. This is the case for the COX metabolites PGI2 and TxA2 , but also for the LO metabolites LTs and LXs, not to mention the production of ATLs by the inflammation-inducible COX-2. While there is no doubts about the importance of COX products in the context of CVDs, as evidenced by the widely recognized efficacy of aspirin, today the importance of the other eicosanoids, such as the ones generated by lipoxygenases, epoxygenases, or by nonenzymatic pathways is still a matter of dispute. This is an area where animal models have shown their limits, and only the identification of specific targets or the development of appropriate pharmacological tools will help to better define their exact role in human pathophysiology. Furthermore, a number of data are emerging demonstrating a crosstalk between LTs and the purinergic system, adding a new step of complexity to the already established intereicosanoid crosstalk. Given this intricate network of cross-reactivity, we believe that a “non specific” inhibition of eicosanoid synthesis is not the best therapeutic strategy to control inflammation and to prevent or treat CVDs. The case of COXIBs and, more generally, the CV effects of tNSAIDs clearly demonstrate that disruption of the “physiological balance” that is clearly behind the multifaceted effects of eicosanoids is a risky strategy. We believe that more selective pharmacological approaches should be conceived and developed, which might include targeting the synthesis of a particular mediator or blocking its receptor.

ACKNOWLEDGMENTS This work was supported in part by grants from Regione Lombardia (SAL-02) and from Fondazione Banca del Monte di Lombardia to G.E. Rovati.

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Val´erie Capra is a senior investigator at the Laboratory of Molecular Pharmacology, Department of Pharmacological Sciences, University of Milan, Italy. She received her degree in Chemistry and Pharmaceutical Technology and her Ph.D. degree in Pharmacology from the University of Milan. She was a postdoctoral fellow at the Institut National de la Sant´e et de la Recherche M´edicale (INSERM) U348, IFR Circulation-Paris-Nord, Hˆopital Lariboisi`ere, Paris, France. Her main interest concerning eicosanoids including cysteinyl-leukotrienes, thromboxane A2 , and prostacyclin. Focus at present is the understanding at the molecular level of how thromboxane A2 receptor and variants are activated, regulated, signals, and oligomerize and their role in inflammatory disease. Magnus B¨ack is Associate Professor of Cardiology at the Karolinska University Hospital and leader of the Cardiovascular Eicosanoid Research Team at the Center for Molecular Medicine at Karolinska Institutet, Stockholm, Sweden. He has previously been a fellow in cardiology and cardiovascular research at Bichat University Hospital and INSERM Unit 698 in Paris, France. His present work is combining clinical work in the coronary intensive care unit, with basic research focused on the role of leukotrienes in atherosclerosis. He is a nucleus member in the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology and the chairman of the Nomenclature Committee for Leukotriene and Lipoxin Receptors of the International Union of Basic and Clinical Pharmacology (IUPHAR). Medicinal Research Reviews DOI 10.1002/med

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Silvia Stella Barbieri is a senior investigator at the Laboratory of Cell Biology and Biochemistry of Atherothrombosis, Centro Cardiologico Monzino IRCCS, Milan, Italy. She received her degree in Chemistry and Pharmaceutical Technology and her Ph.D. degree in Pharmacology from the University of Milan. She was a postdoctoral fellow at the Weill Medical College of Cornell University, New York, NY. Her main research interest concerning eicosanoid metabolism and their pathophysiological role in the atherothrombotic disease. Marina Camera is assistant Professor of Pharmacology at the Universit`a degli Studi di Milano, Italy, and Scientific Coordinator of the Unit of Cellular Biology and Biochemistry of atherothrombosis, Centro Cardiologico Monzino IRCCS. She received her B. Sc. degree in Biological Sciences and her Ph.D. degree in Biotechnology applied to Pharmacology and Cellular and Molecular Biotechnology from the Universit`a degli Studi di Milano. She was a postdoctoral fellow in the Division of Hematology and Oncology at Cornell University Medical College, New York, NY and in the Division of Thrombosis Research and Molecular Cardiology, Department of Medicine, at the Mount Sinai School of Medicine, New York, NY. Her main research interest is focused on the biochemical, cellular, and molecular mechanisms involved in the development and progression of the atherothrombotic disease, with a special focus on the regulation and pharmacological modulation of the procoagulant properties of blood cells and cells of the vessel wall. Elena Tremoli is currently Professor of Pharmacology, Chief Laboratory of Pharmacology of Thrombosis and Atherosclerosis, Department of Pharmacological Sciences, Chief Laboratory of Cellular Biology and Biochemestry of athero-thrombosis, Centro Cardiologico Monzino IRCCS, Scientific Coordinator of the research at Centro Cardiologico Monzino IRCCS, and Scientific Director of the Center of Pharmacological Research for the Study and Prevention of Cardiovascular Diseases. Her main research is focused on atherothrombotic complications in cardiovascular disease with particular reference to the contribution of lipids and lipids mediators to cell function and to the identification of biomarkers of this disease. G. Enrico Rovati is an associate Professor of Pharmacology at University of Milan and chief of the Laboratory of Molecular Pharmacology, Department of Pharmacological Sciences, University of Milan, Italy. He received his degree in Medicine from the University of Pavia and his Ph.D. degree in Pharmacology from the University of Milan. He was a postdoctoral fellow at the Laboratory of Theoretical and Physical Biology, NICHD, NIH, Bethesda, MD. His interests have focused on the application of computational approaches to pharmacological sciences and on the theoretical and regulatory aspects of G protein-coupled receptors function. He is member of the Nomenclature Committee for Leukotriene and Lipoxin Receptors of the International Union of Basic and Clinical Pharmacology (IUPHAR).

NOTE ADDED IN PROOF Since the submission of the manuscript for this article, a new paper has been published shedding light on the role of cysLTs in CVDs. In this observational study the authors found that montelukast use was associated with a decreased risk of ischemic stroke and a decreased risk of MI in males.690

Medicinal Research Reviews DOI 10.1002/med