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Effects of Diabetic HDL on Endothelial Cell Function Dan He1, Bing Pan1, Hui Ren2 and Lemin Zheng1,* 1
The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing 100191, China; 2Auckland Bioengineering Institute, the University of Auckland, Auckland 1142, New Zealand Abstract: Type 2 diabetes mellitus (T2DM) is accompanied by dysfunctional high-density lipoprotein (HDL) and this is characterized by alterations in its composition and structure compared with HDL from normal subjects (N-HDL). HDL from diabetic subjects (D-HDL) has a diminished endothelial protective capacity including reducted ability to exert antioxidative activity, stimulate endothelial cell (EC) production of nitric oxide (NO) and endothelium-dependent vasomotion, promote endothelial progenitor cell (EPC)-mediated endothelial repair. In addition, D-HDL promotes EC proliferation, migration and adhesion to the matrix. The present review provides an overview of these effects of diabetic HDL on EC function, as well as the possible changes of D-HDL structure and composition which may be responsible for the diminished endothelial protective capacity of D-HDL.
Keywords: Diabetes mellitus, dysfunction, endothelial dysfunction, high-density lipoprotein. INTRODUCTION T2DM represents a high risk factor for the development of atherosclerotic and thromboembolic macro/micro-angiopathy [1], resulting in coronary artery, cerebrovascular and peripheral vascular disease which make a major contribution to diabetic mortality. Endothelial dysfunction is critically involved in the pathogenesis of diabetic macro/micro-angiopathy through an inappropriate modulation of vascular tone and structure, including vessel integrity, vascular remodeling and growth, cell adhesion and proliferation, immune and inflammatory responses [1-4]. N-HDL clinically and experimentally exerts direct and pleiotropic endothelial protective effects on activating NO synthase and endothelium-dependent vasomotion [5], exerting antioxidant and anti-inflammatory activities [6], enhancing EPC-mediated endothelial repair, and stimulating EC proliferation and migration [7, 8]. However, T2DM is associated with lipid metabolism disorders, including increased low-density lipoprotein (LDL) levels, low HDL levels, and increased triglycerides (TGs) which are a major risk factor for coronary disease. T2DM is linked to dysregulation in HDL metabolism and production of dysfunctional HDL with impaired endothelial protective features and abnormal morphology and structure [9]. This review summarizes the effect of D-HDL on alteration in EC function, and the possible changes of
*Address correspondence to this author at The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing 100191, China; Tel: 086-010-82805452; Tel: 086-010-82802769; E-mail:
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D-HDL structure and composition in comparison with N-HDL which may be responsible for these altered functions. In addition, the importance of evaluating HDL function in potential HDL-targeted therapies to restore its endothelial protective effects is discussed. D-HDL REDUCES ENDOTHELIAL NO PRODUCTION AND ENDOTHELIUM-DEPENDENT VASODILATION Endothelial NO is of great significance in the regulation of vascular tone and structure. Endothelial dysfunction primarily is a reflection of the diminished availability of NO, a major endothelium-derived vasoactive mediator for endothelium-dependent vasodilation and other atheroprotective properties [10]. Evidence suggested that HDL may stimulate eNOS mediated NO production via endothelial scavenger receptor class B type I (SR-BI) in human ECs while eNOS activity could also be upregulated by HDL through regulation of phosphorylation sites [11-13]. However, experimental studies showed that D-HDL loses its capacity to directly stimulate endothelial NO production in marked contrast to the effects observed with N-HDL, thereby resulting in impaired endothelium-dependent vasodilation of radial artery [14]. Perségol L. et al. [15] demonstrated the inability of D-HDL to counteract the inhibitory effect of oxidized LDL on endothelium-dependent vasorelaxation and this was inversely correlated with the TG content of HDL. The underlying mechanism could be that the enrichment in TGs likely impaired the anti-oxidant effect of N-HDL and its interaction with cell surface receptors, and this was related to the decreased induction of NO synthesis [15, 16]. The lipid composition of HDL is of great importance in determining whether HDL may exert its cardiovascular protective properties normally [9, 17]. One of the main qualitative abnormalities in D-HDL composition is its © 2014 Bentham Science Publishers
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Table 1.
He et al.
Summary of the endothelial protective effects of N-HDL and its alterations in T2DM.
Endothelial Function
Effects of N-HDL
Key Components
Possible Alterations in T2DM
The production of Endothelial NO
N-HDL stimulates eNOS mediated NO production via SR-BI in ECs, and upregulates eNOS activity through regulation of phosphorylation sites [11-13]
apoA-I, MPO, glycation of HDL, oxidation of HDL
Elevated blood glucose levels stimulate the production of ROS, and impair the binding of HDL to the cell surface receptors and the abilities of HDL to promote cholesterol and oxysterols efflux from ECs, involving in the reduced activation of eNOS [19, 20, 44] MPO and its oxidant products markedly impair the ability of HDL to stimulate endothelial NO production [14]
Endotheliumdependent vasodilation
N-HDL stimulates the production of endothelial NO, and counteracts the inhibitory effect of ox-LDL on endothelium-dependent vasorelaxation [15, 16]
apoA-I, TGs, glycation of HDL
The replacement of cholesteryl esters by TGs in HDL attenuates the HDL-mediated protection against LDL oxidation [16] The glycation of HDL significantly abolishes the ability of HDL to counteract the inhibitory effect of ox-LDL on endothelium-dependent vasorelaxation [19]
The maintenance of N-HDL protects ECs from apoptosis the integrity of the and promotes the growth, proliferation vascular endothelium and migration of ECs to maintain the integrity of the endothelial monolayer [23] Endothelial repairing N-HDL at low concentrations capacity of EPCs stimulates EPC tube formation through after vascular injury eNOS activation mechanisms [30] HDL-associated S1P plays a vital role in the capacity of HDL to facilitate EPCs function [29, 31-36]
apoA-I, MPO, The glycation and oxidation of HDL have reduced abilities in glycation of HDL, promoting the ECs proliferation, migration and adhesion to ECM, due oxidation of HDL to the reduced expression of SR-B1 [8,26]
apoA-I, S1P
enrichment of glycation, TGs, and depletion of cholesterol compared with N-HDL [18]. Moreover, TGs appear negatively correlated with the antioxidant properties of HDL and it has been observed that the replacement of cholesteryl esters by TGs in HDL attenuates the HDL-mediated protection against LDL oxidation [16]. Other mechanisms have been shown to contribute to the absence of the vasorelaxant features of D-HDL. It was previously demonstrated that glycation of HDL could significantly abolish the ability of HDL to counteract the inhibitory effect of ox-LDL on endothelium-dependent vasorelaxation in oxidative stress conditions [19]. Glycation of HDL induces changes in several pathways leading to the impaired capacities of D-HDL. The activation of eNOS appears to play a vital role in this process. Conformational modifications induced by the glycation of apolipoprotein A-I (apoA-I) could impair the binding of HDL to the cell surface receptors associated with the signaling pathways to activate eNOS. Impaired abilities of the glycated HDL to promote cholesterol and oxysterols efflux from ECs may also be involved in the reduced activation of eNOS [19, 20]. D-HDL ATTENUATES THE STIMULATION OF EC MIGRATION AND PROLIFERATION In the process of vascular development and pathological angiogenesis, the maintenance of vascular homeostasis and its functional execution depend largely on the integrity of vascular endothelium [21, 22]. Thus, disruption of the endothelial monolayer is an early indicator of the
Circulating EPCs from patients with T2DM were abnormal in function of neovascularization [27], and D-HDL has impaired ability in stimulating circulating EPC-mediated endothelial repair [14] D-HDL carried higher level of S1P compared with N-HDL in the early stage of T2DM while the levels of S1P were decreased in a more serious stage of diabetes [37]
development of vascular disease. Integrity of the vascular endothelium is maintained by proliferation, migration and apoptosis of ECs. The repair of injured vessel walls occurs through the replacement of neighboring mature ECs by proliferation and migration or the repopulation with circulating endothelial progenitor cells (EPCs) [22]. EPCs can differentiate into mature ECs. N-HDL may protect ECs from apoptosis and promote the growth, proliferation and migration of ECs to maintain the integrity of the endothelial monolayer [23]. SR-BI mediates the direct actions of HDL on endothelium and is responsible for initiating signaling in endothelium through Src activation, resulting in parallel activation of Akt kinase and mitogen-activated kinases [24, 25]. PDZK1, the SR-BI adaptor protein, also plays a central role in the promotion of vascular health by HDL [24]. These signaling events initiate EC migration in a NO-independent manner through the eNOS stimulation and activation of Rac GTPase [23-25]. We previously showed that glycation and oxidation levels were much higher in D-HDL compared to N-HDL [8, 26]. N-HDL enhanced the proliferation and migration activities of ECs while D-HDL, glycated HDL (G-HDL), and oxidized HDL (Ox-HDL) had reduced abilities in promoting the ECs proliferation and migration. In addition, D-HDL had impaired capacity to promote EC adhesion to ECM via down regulation of integrin αv. These deleterious effects of D-HDL were associated with reduced expression of endothelial SR-BI located on the cell membrane and SR-
Effects of Diabetic HDL on Endothelial Cell Function
Cardiovascular & Haematological Disorders-Drug Targets, 2014, Vol. 14, No. 1
B1 enriched in EC caveolae. Additionally, down regulation of SR-BI could diminish the capacity of D-HDL to activate Akt. D-HDL IMPAIRS CAPACITY OF EPCs
ENDOTHELIAL
REPAIR
As indicated above circulating EPCs promote endothelial integrity. Tepper O.M. et al. [27] illustrated that the circulating EPCs from T2DM were abnormal in function of adhesion to endothelium, proliferation, and tubulization which may account for the impaired neovascularization. Sorrentino S.A. et al. [14] examined the different effects of HDL separately isolated from healthy subjects (n=10) and patients with T2DM (n=33) on the circulating EPC-mediated endothelial repair. They observed that HDL from healthy subjects, but not from diabetic patients, stimulated circulating EPC-mediated endothelial repair, and the effect of N-HDL on early EPC-mediated endothelial repair was also mediated by NO production of circulating EPCs. As reduced number and endothelial repair ability of circulating EPCs are strongly associated with endothelial dysfunction and high cardiovascular risk, one of the endothelial protective effects of HDL is its capacity to increase the number of circulating EPCs [28] as well as to promote endothelial regeneration [29]. Increasing levels of HDL by systemic infusion of reconstituted HDL (rHDL) lead to the improvement of EPC availability in patients with T2DM, implying a possible HDL-increasing strategy in acute settings [28]. However, it is important to note that HDL may exert paradoxical effects at different concentrations. Recent studies demonstrated the concentration-related biphasic vascular effects of HDL in the absence of oxLDL. N-HDL at low concentrations stimulated EPC tube formation through eNOS activation mechanisms, whereas HDL at normal to high physiological concentrations impaired EPCs and related angiogenesis by activating Rho-associated kinase pathways along with consequent inhibition of eNOS activity [30]. Sphingosine-1-phosphate (S1P) is a bioactive lipid predominantly integrated with HDL in plasma. HDLassociated S1P plays a vital role in the capacity of HDL to facilitate EPCs function. 65% of the S1P in blood is associated with the lipoproteins LDL, VLDL, and HDL, with the bulk of the lipoprotein-associated S1P (～54%) bound to HDL [29, 31]. Walter D.H. et al demonstrated that S1P could stimulate the angiogenic activity and neovascularization capacity of cultured EPCs by activating the CXCR4 dependent JAK2 signaling pathway via activation of the S1P3 receptor [32]. In addition, It is suggested that S1P could significantly upregulate the expression of COX-2 through S1P receptors and the production of PGI2 by the activation of p38 MAPK, ERK1/2 and CREB signaling pathways in ECs, both of which could provide beneficial anti-atherogenic effects on vasodilation, and inhibition of platelet aggregation [33-36]. We recently demonstrated that D-HDL carried higher level of S1P compared with N-HDL in the early stage of T2DM, indicating one of the body’s compensatory
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mechanisms preventing or delaying complications against the disease. The levels of HDL-associated S1P were decreased in subjects of T2DM accompanied with atherosclerosis which indicated a more serious stage of diabetes, compared with that of early T2DM [37]. It makes sense that the functions of D-HDL in vascular system in T2DM vary from even more protective than the N-HDL due to a compensatoryprotection strategy of human body at the very beginning to gradually impaired as a result of decompensation along with the different stages of T2DM, since T2DM is a chronic disease. IMPACT OF MODIFIED D-HDL ON PEROXIDATION AND GLYCATION OF ECs The key abnormalities of HDL are characterized by TG enrichment, depletion in cholesteryl esters with conformational alterations of apoA-I, glycation of apolipoproteins or HDLassociated enzymes, oxidative modifications of HDL lipids, apolipoproteins or enzymes [38]. Several studies provided insight into the association of lipid peroxidation and glycation of HDL leading to the altered HDL functions. These studies suggested that an increase in lipid peroxidation and glycation of D-HDL [14, 39]. Myeloperoxidase (MPO) and its oxidant products appear to exert potent effects in the promotion of lipid peroxidation. It is proposed that serum MPO levels serve as a strong and independent predictor of endothelial dysfunction in humans subjects [40-41]. ApoA-I, the main apolipoprotein constituent of HDL, has also been examined as a selective target for MPO-catalyzed oxidation and functional impairment in subjects with cardiovascular disease [42]. We previously demonstrated that MPO-catalyzed nitration and chlorination of HDL were negative modulators of EC proliferation and migration, rendering oxidized HDL dysfunctional [43]. In addition, other studies revealed that both MPO-catalyzed nitrating and chlorinating oxidants markedly impaired its ability to stimulate endothelial NO production. Both the content and activity of MPO associated with HDL were increased in D-HDL compared with N-HDL [14]. All these studies are compatible with the notion that MPO and its oxidant products play a vital role in altered endothelial effects of D-HDL. Accumulating evidence suggested that persistently elevated blood glucose levels may stimulate the production of reactive oxidant species (ROS) via multiple pathways, thus contributing to uncoupling of mitochondrial oxidative phosphorylation and eNOS activity, reducing NO availability, and generating further ROS [44]. Additionally, highly reactive and toxic α-oxoaldehydes such as methylglyoxal (MG) and glycolaldehyde (GA) derived from the reduction of sugars are generated in the process as well. The complex reaction of oxidation, dehydration and aggregation, all lead to irreversible, non-enzymatic glycation of plasma proteins, including apoA-I [45]. Advanced glycation end products (AGEs) modification of apoA-I may result in dysfunction of EC in T2DM. Early studies by Matsunaga T. et al. [46] demonstrated that
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additional oxidation of HDL under hyperglycemic conditions was prone to induce endothelial apoptosis via a mitochondrial dysfunction, and this resulted in the deterioration of vascular function. Non-enzymatic glycation of apoA-I impairs the anti-inflammatory and antioxidant properties of HDL [39], and the ability of LCAT to convert discoidal HDL into spherical HDL which is required for cholesterol efflux from macrophages [47]. In addition, D-HDL exhibits a reduced binding capacity to ECs, as well as a weak or even no inhibitory effect on EC superoxide production or NADPH oxidase activity, implying a loss of antioxidant effects of HDL on endothelium in diabetic patients [14].
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SUMMARY AND OUTLOOK Over the past two decades, consistent cross-sectional and prospective epidemiological studies have demonstrated the pathogenesis of endothelial dysfunction in T2DM is intricate and multifactorial. The presence of heterogeneous HDL in T2DM and its potential role in the progression of T2DM is currently an active research field. The impaired endothelialvasoprotective capacity of HDL is attributed primarily to the abnormalities in HDL composition and structure and this is partly due to modification via peroxidation and glycation in D-HDL. T2DM is a chronic disease and the human body exhibits complex regulatory mechanisms under pathological conditions. The underlying specific molecular mechanisms of how modified or altered HDL functions and is metabolized on ECs is still obscure. Moreover, it is necessary to further investigate whether HDL composition and structure vary in different stages of T2DM and how these changes affect the EC function. Further clinical research, particularly in vivo, needs to be performed in larger sample sizes of T2DM patients and extended to provide a more broad analysis for more definitive conclusions.
[9]
[10] [11]
[12] [13]
[14]
CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest.
[15]
ACKNOWLEDGEMENTS This work was supported by Grants 2010CB912504 and 2011CB503900 from “973” National S&T Major Project, 81170101, 81172500, and 81370235 from the National Natural Science Foundation of China. REFERENCES [1] [2] [3] [4] [5]
Laight, D.W.; Carrier, M.J.; Anggård, E.E. Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy, Diabetes Metab. Res. Rev., 1999, 15, 274-282. Bonetti, P.O.; Lerman, L.O.; Lerman, A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler. Thromb. Vasc. Biol., 2003, 23, 168-175. Félétou, M.; Vanhoutte, P.M., Endothelial dysfunction: a multifaceted disorder (the Wiggers award lecture). Am. J. Physiol. Heart Circ. Physiol., 2006, 291, H985-H1002. Sena, C.M.; Pereira, A.M.; Seica, R. Endothelial dysfunction - A major mediator of diabetic vascular disease, Biochim. Biophys. Acta., 2013, 1832, 2216-2231. Nofer, J.R.; van der Giet, M.; Tolle, M.; Wolinska, I.;von Wnuck Lipinski, K.; Baba, H.A.; Tietge, U.J.;Godecke. A.; Ishii, I.;
[16]
[17]
[18]
[19]
[20]
He et al. Kleuser, B.; Schafers, M.; Fobker,M.; Zidek, W.; Assmann, G.; Chun, J.; Levkau, B. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J. Clin. Invest., 2004, 113, 569 -581. Terasaka, N.; Wang, N.; Yvan-Charvet, L.; Tall, A.R. High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1. Proc. Natl. Acad. Sci. US A, 2007, 104, 15093-15098. Giannotti, G.; Doerries, C.; Mocharla, P.S.; Mueller, M.F.; Bahlmann, F.H.; Horvàth, T.; Jiang, H.; Sorrentino, S.A.; Steenken, N.; Manes, C.; Marzilli, M.; Rudolph, K.L.; Lüscher, T.F.; Drexler, H.; Landmesser, U. Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: relation to endothelial dysfunction. Hypertension, 2010, 55, 1389-1397. Pan, B.; Ma, Y.; Ren, H.; He, Y.; Wang, Y.; Lv, X.; Liu, D.; Ji, L.; Yu, B.; Wang, Y.; Chen, Y.E.; Pennathur, S.; Smith, J.D.; Liu, G.; Zheng, L. Diabetic HDL is dysfunctional in stimulating endothelial cell migration and proliferation due to down regulation of SR-BI expression. PLoS One, 2012, 7, e48530. Van Linthout, S.; Spillmann, F.; Schultheiss, H.P.; Tschöpe, C. High-density lipoprotein at the interface of type 2 diabetes mellitus and cardiovascular disorders. Curr. Pharm. Des., 2010, 16, 15041516. Landmesser, U.; Hornig, B.; Drexler, H. Endothelial function: a critical determinant in atherosclerosis? Circulation, 2004, 109, II27-II33. Drew, B.G.; Fidge, N.H.; Gallon-Beaumier, G.; Kemp, B.E.; Kingwell, B.A. High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation. Proc. Natl. Acad. Sci. USA, 2004, 101, 6999-7004. Riwanto, M.; Landmesser, U. High-density lipoproteins and Endothelial Functions: Mechanistic Insights and Alterations in Cardiovascular Disease. J. Lipid Res., 2013, 54(12), 3227-43. Nofer, J.R.; van der Giet, M.; Tölle, M.; Wolinska, I.; von Wnuck Lipinski, K.; Baba, H.A.; Tietge, U.J.; Gödecke, A.; Ishii, I.; Kleuser, B.; Schäfers, M.; Fobker, M.; Zidek, W.; Assmann, G.; Chun, J.; Levkau, B. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J. Clin. Invest., 2004, 113, 569-581. Sorrentino, S.A.; Besler, C.; Rohrer, L.; Meyer, M.; Heinrich, K.; Bahlmann, F.H.; Mueller, M.; Horváth, T.; Doerries, C.; Heinemann, M.; Flemmer, S.; Markowski, A.; Manes, C.; Bahr, M.J.; Haller, H.; von Eckardstein, A.; Drexler, H.; Landmesser, U. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation, 2010, 121, 110122. Perségol, L.; Vergès, B.; Foissac, M.; Gambert, P.; Duvillard, L. Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation. Diabetologia, 2006, 49, 1380-1386. Nobécourt, E.; Jacqueminet, S.; Hansel, B.; Chantepie, S.; Grimaldi,A.; Chapman, M.J.; Kontush, A. Defective antioxidative activity of small dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and hyperglycaemia. Diabetologia, 2005, 48, 529-538. Baker, P.W.; Rye, K.A.; Gamble, J.R.; Vadas, M.A.; Barter, P.J. Ability of reconstituted high density lipoproteins to inhibit cytokineinduced expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. J. Lipid Res., 1999, 40, 345-353. Gowri, M.S.; Van der Westhuyzen, D.R.; Bridges, S.R.; Anderson, J.W. Decreased protection by HDL from poorly controlled type 2 diabetic subjects against LDL oxidation may Be due to the abnormal composition of HDL. Arterioscler. Thromb. Vasc. Biol., 1999, 19, 2226-2233. Brindisi, M.C.; Duvillard, L.; Monier, S.; Vergès, B.; Perségol, L. Deleterious effect of glycation on the ability of HDL to counteract the inhibitory effect of oxidized LDL onendothelium-dependent vasorelaxation. Diabetes Metab. Res. Rev., 2013, 29(8), 618-2 Duell, P.B.; Oram, J.F.; Bierman, E.L. Nonenzymatic glycosylation of HDL and impaired HDL-receptor-mediated cholesterol efflux. Diabetes, 1999, 40, 377-384.
Effects of Diabetic HDL on Endothelial Cell Function [21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31] [32]
[33]
Cardiovascular & Haematological Disorders-Drug Targets, 2014, Vol. 14, No. 1
Triggle, C.R.; Samuel, S.M.; Ravishankar, S.; Marei, I.; Arunachalam, G.; Ding, H.The endothelium: influencing vascular smooth muscle in many ways. Can. J. Physiol. Pharmacol., 2012, 90, 713-738. Tao, J.; Yan, C.; Tian, X.; Liu, S.; Li, Y.; Zhang, J.; Sun, M.; Ma, X.; Han, Y. CREG Promotes the Proliferation of Human Umbilical Vein Endothelial Cells through the ERK/Cyclin E Signaling Pathway. Int. J. Mol. Sci., 2013, 14, 18437-18456. Seetharam, D.; Mineo, C.; Gormley, A.K.; Gibson, L.L.; Vongpatanasin, W.; Chambliss, K.L.; Hahner, L.D.; Cummings, M.L.; Kitchens, R.L.; Marcel, Y.L.; Rader, D.J.; Shaul, P.W. Highdensity lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-Btype I. Circ. Res., 2006, 98, 63-72. Zhu, W.; Saddar, S.; Seetharam, D.; Chambliss, K.L.; Longoria, C.; Silver, D.L.; Yuhanna, I.S.; Shaul, P.W.; Mineo, C. The cavenger receptor class B type I adaptorprotein PDZK1 maintains endothelial monolayer integrity. Circ. Res., 2008, 102, 480-487. Mineo, C.; Yuhanna, I.S.; Quon, M.J.; Shaul, P.W., High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases. J. Biol. Chem., 2003, 278, 9142-9149. Pan, B.; Ren, H.; Ma, Y.; Liu, D.; Yu, B.; Ji, L.; Pan, L.; Li, J.; Yang, L.; Lv, X.; Shen, X.; Chen, B.; Zhang, Y.; Willard, B.; He, Y.; Zheng, L. High-density lipoprotein of patients with type 2 diabetes mellitus elevates the capability of promoting migration and invasion of breast cancer cells. Int. J. Cancer., 2012, 131, 7082. Tepper, O.M.; Galiano, R.D.; Capla, J.M.; Kalka, C.; Gagne, P.J.; Jacobowitz, G.R.; Levine, J.P.; Gurtner, G.C. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation, 2002, 106, 2781-2786. van Oostrom, O.; Nieuwdorp, M.; Westerweel, P.E.; Hoefer, I.E.; Basser, R.; Stroes, E.S.; Verhaar, M.C. Reconstituted HDL increases circulating endothelial progenitor cells in patients with type 2 diabetes. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 1864-1865. Murata, N.; Sato, K.; Kon, J.; Tomura, H.; Yanagita, M.; Kuwabara, A.; Ui, M.; Okajima, F. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem. J., 2000, 352, 809-815. Huang, C.Y.; Lin, F.Y.; Shih, C.M.; Au, H.K.; Chang, Y.J.; Nakagami, H.; Morishita, R.; Chang, N.C.; Shyu, K.G.; Chen, J.W. Moderate to high concentrations of high-density lipoprotein from healthy subjects paradoxically impair humanendothelial progenitor cells and related angiogenesis by activating Rho-associated kinase pathways. Arterioscler. Thromb. Vasc. Biol., 2012, 32, 2405-2417. Argraves, K.M.; Argraves, W.S. HDL serves as a S1P signaling platform mediating a multitude of cardiovascular effects. J. Lipid Res., 2007, 48, 2325-2333. Walter, D.H.; Rochwalsky, U.; Reinhold. J.; Seeger, F.; Aicher, A.; Urbich, C.; Spyridopoulos, I.; Chun, J.; Brinkmann, V.; Keul, P.; Levkau, B.; Zeiher, A.M.; Dimmeler, S.; Haendeler, J. Sphingosine1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 275-282. Rodríguez, C.; González-Díez, M.; Badimon, L.; Martínez-González, J. Sphingosine-1-phosphate: A bioactive lipid that confers highdensity lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin. Thromb. Haemost., 2009, 101, 665-673.
Received: 20 January, 2012
[34]
[35]
[36]
[37]
[38] [39]
[40]
[41] [42]
[43]
[44] [45]
[46]
[47]
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Serrano-Sanchez, M.; Tanfin, Z.; Leiber, D. Signaling pathways involved in sphingosine kinase activation and sphingosine-1phosphate release in rat myometrium in late pregnancy: role in the induction of cyclooxygenase 2. Endocrinology, 2008, 149, 46694679. Nodai, A.; Machida, T.; Izumi, S.; Hamaya, Y.; Kohno, T.; Igarashi, Y.; Iizuka, K.; Minami, M.; Hirafuji, M. Sphingosine 1phosphate induces cyclooxygenase-2 via Ca2+-dependent, but MAPK-independent mechanism in rat vascular smooth muscle cells. Life Sci., 2007, 80, 1768-1776. Liu, D.; Ji, L.; Wang, Y.; Zheng, L. Cyclooxygenase-2 expression, prostacyclin production and endothelial protection of high-density lipoprotein. Cardiovasc. Hematol. Disord. Drug Targets, 2012, 12, 98-105. Tong, X.; Peng, H.; Liu, D.; Ji, L.; Niu, C.; Ren, J.; Pan, B.; Hu, J.; Zheng, L.; Huang, Y. High-density lipoprotein of patients with Type 2 diabetes mellitus upregulates cyclooxgenase-2 expression and prostacyclin I-2 release in endothelial cells: relationship with HDL-associated sphingosine-1-phosphate. Cardiovasc. Diabetol., 2013,12, 27. Kontush, A.; Chapman, M.J. Why is HDL functionally deficient in type 2 diabetes? Curr. Diab. Rep., 2008, 8, 51-59. Liu, D.; Ji, L.; Zhang, D.; Tong, X.; Pan, B.; Liu, P.; Zhang, Y.; Huang, Y.; Su, J.; Willard, B.; Zheng, L. Nonenzymatic glycation of high-density lipoprotein impairs its anti-inflammatory effects in innate immunity. Diabetes Mateb. Res. Rev., 2012, 28, 186-195. Vita, J.A.; Brennan, M.L.; Gokce, N.; Mann, S.A.; Goormastic, M.; Shishehbor, M.H.; Penn, M.S.; Keaney, JF J.r.; Hazen, S.L. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation, 2004, 110, 1134-1139. Nicholls, S.J.; Hazen, S.L. The role of myeloperoxidase in the pathogenesis of coronary artery disease. Japan J. Infect. Dis., 2004, 57, S21-S22. Zheng, L.; Nukuna, B.; Brennan, M.L.; Sun, M.; Goormastic, M.; Settle, M.; Schmitt, D.; Fu, X.; Thomson, L.; Fox, P.L.; Ischiropoulos, H.; Smith, J.D.; Kinter, M.; Hazen, S.L. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J. Clin. Invest., 2004, 114, 529-541. Pan, B.; Yu, B.; Ren, H.; Willard, B.; Pan, L.; Zu, L.;, Shen, X.; Ma, Y.; Li, X.; Niu, C.; Kong, J.; Kang, S.;, Eugene Chen, Y.; Pennathur, S.; Zheng, L. High-density lipoprotein nitration and chlorination catalyzed by myeloperoxidase impair its effect of promoting endothelial repair. Free Radic Biol Med, 2013, 60, 272281. Woodman, R.J.; Chew, G.T.; Watts, G.F. Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy. Drugs, 2005, 65, 31-74. Kurosaki, Y.; Tsukushi, T.; Munekata, S.; Akahoshi, T.; Moriya, T.; Ogawa, Z. Semiquantitative analysis of apolipoprotein A-I modified by advanced glycation end products in diabetes mellitus. J. Clin. Lab. Anal., 2013, 27, 231-236. Matsunaga, T.; Iguchi, K.; Nakajima, T.; Koyama, I.; Miyazaki, T.; Inoue, I.; Kawai, S.; Katayama, S.; Hirano, K.; Hokari, S.; Komoda, T. Glycated high-density lipoprotein induces apoptosis of endothelial cells via a mitochondrial dysfunction. Biochem. Biophys. Res. Commun., 2001, 287, 714-720. Rye. K.A. Biomarkers associated with high-density lipoproteins in atherosclerotic kidney disease. Clin. Exp. Nephrol., 2014, 18(2), 247-50.
Revised: 15 October, 2012
Accepted: 17 October, 2012
