Resident Cardiac Mast Cells: Are They the ... - Wiley Online Library

© 2007 The Authors Journal compilation © 2007 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 5–9

Doi: 10.1111/j.1742-7843.2007.00147.x

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Resident Cardiac Mast Cells: Are They the Major Culprit in the Pathogenesis of Cardiac Hypertrophy? Pitchai Balakumar1, Amrit Pal Singh2, Subrahmanya S. Ganti1, Pawan Krishan2, Subbiah Ramasamy3 and Manjeet Singh1 1

ISF Institute of Pharmaceutical Sciences and Drug Research, Moga, Punjab, 2Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, and 3Department of Biochemistry, School of Biological Sciences, Madurai Kamraj University, Madurai, India (Received May 22, 2007; Accepted July 4, 2007) Abstract: Mast cells originate from pluripotent progenitor cells in bone marrow and are major players in the inflammation process. The involvements of mast cells in various cardiovascular complications such as arrhythmias, ischaemia reperfusion injury and graft rejection are well documented. Moreover, recent studies suggest the involvement of mast cells in cardiac hypertrophy and heart failure. The present review focuses on the role of mast cells in the development of cardiac hypertrophy and heart failure.

Mast cells were first described by Paul Ehrlich in 1879; they are multi-effector cells playing an important role in inflammation [1,2]. Mast cells originate from pluripotent progenitor cells in the bone marrow. Subsequently, mast cell precursors migrate to various tissues and develop as mature cells [3]. The mature mast cells do not circulate in blood and are confined to peripheral tissues, but they retain their proliferative ability [4,5]. Mast cells are localized to various organs rich in connective tissue, such as lungs, cardiovascular tissues, gastrointestinal tract, skin, uterus and prostate [6,7]. Distinct mast cell heterogeneity is observed in rodents and human beings. In rodents, mast cells (MC) are classified as connective tissue mast cells and mucosal mast cells; however, in humans, mast cells are classified on the basis of protease enzymes such as tryptase (MCT), chymase (MCC) or both chymase and tryptase (MCTC ) [8,9]. The human heart contains 90% of MCTC type mast cells [10]. Cardiac mast cells participate in various physiological functions, such as angiogenesis [11], formation of atrial natriuretic peptide [12] and angiotensin II [13,14]. The role of cardiac mast cells has been implicated in various pathophysiological processes, such as ischaemia reperfusion injury [15], arrhythmias [16] and graft rejection after heart transplant [17,18]. In addition, recent studies suggest that mast cells have a significant role in the pathogenesis of dilated cardiomyopathy [19], cardiac

Author for correspondence: Pitchai Balakumar, Cardiovascular Pharmacology Division, I.S.F. Institute of Pharmaceutical Sciences and Drug Research, Moga 142 001, India (fax +91 163 62365 64, e-mail [email protected]).

hypertrophy and heart failure [20–23]. The present review delineates the role of mast cells in the pathogenesis and progression of cardiac hypertrophy and heart failure. Cardiac hypertrophy and signalling pathways The cardiac hypertrophy is an adaptive response of the heart against haemodynamic overload; but chronic hypertrophic signals involve various maladaptive signalling pathways such as Rho-kinase, caspase-3, poly(ADP-ribose) polymerase (PARP), tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, IL-18, calcineurin, mitogen-activated protein kinase (MAPK), Janus kinase/signal transducers and activators of transcription (JAK/STAT), Wnt/Frizzled pathway and various neurohormones, which all together lead to pathological cardiac hypertrophy followed by cardiac dysfunction and heart failure [24–36]. Various interventions such as fasudil, an inhibitor of Rho-kinase; ACDEVD-CHO, an inhibitor of caspase-3; 3-aminobenzamide and 5-aminoisoquinoline, inhibitors of PARP; pentoxifylline, an inhibitor of TNF-α; and AG 490, an inhibitor of JAK have been noted to attenuate the pressure overload-induced experimental cardiac hypertrophy [24–28,35]. The pathological cardiac hypertrophy involves up-regulation of foetal genes such as β-myosin heavy chain, skeletal α-actin and atrial natriuretic peptide along with down-regulation of α-myosin heavy chain and sarcoplasmic endoplasmic reticulum Ca2+ ATPase (SERCA) [37,38]. Moreover, expression of various transcriptional factors such as transcription enhancer factor-1 (TEF-1), myocyte enhancer factor-2 (MEF-2), divergent transcriptional enhancer factor-1 (DTEF-1), specificity

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protein-1 (Sp-1), GATA-4, NKX2-5, HAND and Smads are up-regulated in pathological cardiac hypertrophy [39,40]. Mediators released from mast cells Mast cells are an important source of an array of cytokines, growth factors and chemokines [1]. Some mediators released from mast cells are preformed and stored in granules inside the mast cells, where a few undergo de novo synthesis. Mediators such as histamine, serotonin, adenosine, heparin, tryptase, chymase, elastase, carboxypeptidase A and B, cathepsin, β-galactosidase, β-glucuronidase, chemotactic factors for eosinophils and neutrophils are stored inside mast cells and are released on mast cell degranulation. On the other hand, various lipid mediators such as platelet activating factor (PAF), prostaglandin D2 (PGD2), leukotriene B4 (LTB4), LTC4, LTD4, thromboxane A2 and B2 follow de novo synthesis. Moreover, mast cells are noted to release various cytokines such as TNF-α, IL-1, IL-6, transforming growth factor (TGF)-β and other growth factors including vascular endothelial growth factor and basic fibroblast growth factor [1,9]. It is interesting to note that mast cell degranulation does not lead to their death and mast cells in both rodents and human beings are reported to reconstitute their granules following their degranulation [41]. Role of mast cells in cardiac hypertrophy and failure A significant increase in mast cell density and extent of hypertrophy and failure has been observed in heart [22,23]. Moreover, increased mast cell degranulation is associated with increased mast cell density [19]. The mechanism of this increase in density following degranulation remains to be explored. However, it is hypothesized that mast cell degranulation may release some mediators such as TGF-β and tryptase that cause maturation and differentiation of immature resident mast cells along with chemotaxis of circulating mast cell precursors [42,43]. Histamine is a major mediator released from mast cell degranulation in heart [44]. Histamine induces the expression of c-fos, an early responsive gene involved in the induction of cardiac hypertrophy [45]. In a recent study, famotidine, a histamine H2 receptor antagonist, has prevented ventricular remodelling in congestive heart failure patients suggesting the role of histamine in heart failure [46]. Chymase, a proteolytic enzyme, is stored inside mast cells and activated on mast cell degranulation and catalyses the conversion of angiotensin I to angiotensin II independent of angiotensinconverting enzyme [47]. In human heart, 2-fold increases in chymase levels are observed in ventricles than atria and 80% of angiotensin II generation in left ventricle is carried out by chymase [48,49]. The compound named SUNC8257, a specific inhibitor of chymase, has been shown to prevent cardiac fibrosis and to improve diastolic dysfunction [50]. Mast cell release product such as TGF-β is involved in induction of cardiac hypertrophy, fibroblast proliferation and collagen synthesis in heart [51–53]. Moreover, chymase-

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derived angiotensin II up-regulates the expression of TGF-β1 mRNA in cardiomyocytes through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [54]. The TGF-β1 elicits its biological response through serine/ threonine kinase receptors such as TβR1 and TβR2 [55]. TGF-β1 binds with TβR2 to form heterodimeric complex with TβR1, which further activates serine/threonine kinase that causes phosphorylation of Smad3. The phosphorylated form of Smad3 forms hetero-oligomer with Smad4 and this complex moves to nucleus and binds with activating transcription factor-2 (ATF-2) to enhance its transcription activity, which is responsible for overexpression of hypertrophic genes [55,56]. Furthermore, TGF-β has been shown to activate TGF-β-activated kinase-1 (TAK-1), which further activates mitogen-activated kinase kinase (MKK)3/6-p38 MAP kinase signalling to induce cardiac hypertrophy [53,57]. The inhibitors of protein kinase C (PKC) such as GO6976 and GF109203X have been noted to inhibit TGFβ1-induced TAK-1 activity and subsequent downstream signalling pathway involving ATF-2, thus suggesting the role of PKC-dependent ATF-2 activation in the induction of cardiac hypertrophy [57]. Moreover, treatment with PKC inhibitor such as ruboxistaurin (LY333531) has been noted to reduce left ventricular fibrosis and dysfunction in rats [58]. Tumour necrosis factor-α is a major release product of mast cell degranulation [15]. Although all cardiac cells have the ability to generate TNF-α, evidence indicates that constitutive expression of TNF-α is additionally localized in cardiac mast cells [13,15]. Mast cell stimulation activates TNF-α/NF-κB/IL-6 cascades to induce cardiac hypertrophy [22]. TNF-α induces the activation of p38MAPK, which further activates nuclear factor kappa B (NF-κB) and hypertrophic genes to cause hypertrophy and dysfunction of heart [59,60]. IL-6 family involves a common transducing component such as gp130 to induce cardiac hypertrophy through JAK/STAT pathways [61,62]. Numerous studies suggest mast cells as additional source of renin and mast cell degranulation is capable of releasing renin, which further activates local renin angiotensin system in heart [14,16]. Thus, the local production of angiotensin II in heart may be implicated in the pathogenesis of ventricular hypertrophy [63,64]. Mast cells are known to produce intracellular reactive oxygen species (ROS), which regulate the function of mast cells including their degranulation. However, ROS generated by mast cells are not exported out of cell because of their strong intracellular antioxidant system [65]. Mast cell release products such as TNF-α and angiotensin II are documented to increase ROS production through NADPH oxidase activity [66,67]. The ROS thus generated may activate mast cells through intracellular Ca2+ mobilization [65,68,69]. The ROS are documented to be involved in induction of cardiac hypertrophy by activating tyrosine kinase, PKC and MAPK [70–73]. In contrast, some studies suggest the protective role of mast cells in myocardial remodelling [74,75]. However, mast cell stabilizers have been noted to prevent ventricular remodelling induced by volume overload and autoimmune


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MAST CELLS AND CARDIAC HYPERTROPHY

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Fig. 1. The signaling mechanisms involved in mast cell degranulation-mediated development of cardiac hypertrophy. Ang II, angiotensin II; ATF-2, activating transcription factor-2; CaMK, calcium-calmodulin-dependent kinase; ERK, extracellular signal-regulated kinase; HDAC, histone deacetylase; IL-6, interleukin-6; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase; NFAT, nuclear factor of activate T-cell; PKC, protein kinase C; ROS, reactive oxygen species; STAT, signal transducers and activators of transcription; TAK-1, TGF-β-activated kinase; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α.

myocarditis-induced cardiomyopathy [19,76]. Moreover, in a recent study, an increased mast cell density and chymase mRNA expression was observed in failing hearts [23], which strongly suggest the involvement of mast cells in the progression of myocardial remodelling. The proposed signalling mechanisms involved in mast cell degranulationmediated development of cardiac hypertrophy have been summarized in fig. 1. In conclusion, mast cells may be one of the culprits involved in the development of cardiac hypertrophy and heart failure. However, further studies are warranted to entirely elucidate the involvement of mast cells in the induction and progression of cardiac hypertrophy and heart failure. Acknowledgements We wish to express our gratefulness to Shri. Parveen Garg, Honorable Chairman, ISF Institute of Pharmaceutical Sciences and Drug Research, Moga, Punjab, for his praiseworthy suggestion and constant support for this study.

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