Platelets as a novel target for PPARγ ligands: Implications for inflammation, diabetes, and cardiovascular disease

BioDrugs

Volumn 20, Issue 4, 2006, Pages 231-241

  Ray, Denise M ^a   Spinelli, Sherry L ^b   O'Brien, Jamie J ^a   Blumberg, Neil ^b   Phipps, Richard P ^a,c  

^a UNIVERSITY OF ROCHESTER   (United States)

^b UNIVERSITY OF ROCHESTER MEDICAL CENTER   (United States)

^c UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE AND DENTISTRY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; CD40 LIGAND; CIGLITAZONE; MURAGLITAZAR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; RAGAGLITAZAR; ROSIGLITAZONE; TESAGLITAZAR; THROMBOXANE A2; TROGLITAZONE;

ANEMIA; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; DIABETES MELLITUS; DYSLIPIDEMIA; EDEMA; FLUID RETENTION; GASTROINTESTINAL SYMPTOM; HUMAN; LIVER TOXICITY; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; THROMBOCYTE; THROMBOGENESIS; WEIGHT GAIN;

ANIMALS; BLOOD PLATELETS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS; DRUG DELIVERY SYSTEMS; HUMANS; INFLAMMATION; LIGANDS; MODELS, BIOLOGICAL; PLATELET AGGREGATION; PPAR GAMMA;

EID: 33745897327     PISSN: 11738804     EISSN: 11738804     Source Type: Journal    
DOI: 10.2165/00063030-200620040-00004     Document Type: Review

References (132)

1. von Daniken A, Lutz WK, Schlatter C. Lack of covalent binding to rat liver DNA of the hypolipidemic drugs clofibrate and fenofibrate. Toxicol Lett 1981; 7: 305-10
2. Issemann I, Green S. Cloning of novel members of the steroid hormone receptor superfamily. J Steroid Biochem Mol Biol 1991; 40: 263-9
3. Braissant O, Foufelle F, Scotto C, et al. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 1996; 137: 354-66
4. Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992; 358: 771-4
5. Barish GD, Narkar VA, Evans RM. PPARδ: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006; 116: 590-7
6. Chung SW, Kang BY, Kim SH, et al. Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-γ and nuclear factor-κ B. J Biol Chem 2000; 275: 32681-7
7. Kelly D, Campbell JI, King TP, et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nat Immunol 2004; 5: 104-12
8. Zhu Y, Qi C, Korenberg JR, et al. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci U S A 1995; 92: 7921-5
9. Fajas L, Auboeuf D, Raspe E, et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem 1997; 272: 18779-89
10. Ricote M, Huang J, Fajas L, et al. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci U S A 1998; 95: 7614-9
11. Akbiyik F, Ray DM, Gettings KF, et al. Human bone marrow megakaryocytes and platelets express PPARγ, and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes. Blood 2004; 104: 1361-8
12. Harris SG, Phipps RP. The nuclear receptor PPAR γ is expressed by mouse T lymphocytes and PPAR γ agonists induce apoptosis. Eur J Immunol 2001; 31: 1098-105
13. Iijima K, Yoshizumi M, Ako J, et al. Expression of peroxisome proliferator-activated receptor γ (PPARγ) in rat aortic smooth muscle cells. Biochem Biophys Res Commun 1998; 247: 353-6
14. Nencioni A, Grunebach F, Zobywlaski A, et al. Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor γ. J Immunol 2002; 169: 1228-35
15. Padilla J, Leung E, Phipps RP. Human B lymphocytes and B lymphomas express PPAR-γ and are killed by PPAR-γ agonists. Clin Immunol 2002; 103: 22-33
16. Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 1998; 391: 79-82
17. Su CG, Wen X, Bailey ST, et al. A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response. J Clin Invest 1999; 104: 383-9
18. Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator- activated receptor γ (PPAR γ). J Biol Chem 1995; 270: 12953-6
19. 2 is a ligand for the adipocyte determination factor PPAR γ. Cell 1995; 83: 803-12
20. 2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 1995; 83: 813-9
21. McIntyre TM, Pontsler AV, Silva AR, et al. Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist. Proc Natl Acad Sci U S A 2003; 100: 131-6
22. Schopfer FJ, Lin Y, Baker PR, et al. Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor γ ligand. Proc Natl Acad Sci U S A 2005; 102: 2340-5
23. Guan Y, Hao C, Cha DR, et al. Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption. Nat Med 2005; 11: 861-6
24. Fagerberg B, Edwards S, Halmos T, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor α/γ agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 2005; 48: 1716-25
25. Skrumsager BK, Nielsen KK, Muller M, et al. Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR α and γ agonist in healthy subjects and patients with type 2 diabetes. J Clin Pharmacol 2003; 43: 1244-56
26. Brand CL, Sturis J, Gotfredsen CF, et al. Dual PPARα/γ activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 2003; 284: E841-54
27. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005; 294: 2581-6
28. Liu H, Zang C, Fenner MH, et al. Growth inhibition and apoptosis in human Philadelphia chromosome positive lymphoblastic leukemia cell lines by treatment with the dual PPARα/γ ligand TZD18. Blood 2006 May 1; 107 (9): 3683-92
29. Rangwala SM, Lazar MA. The dawn of the SPPARMs? Sci STKE 2002; 2002: PE9
30. Nolte RT, Wisely GB, Westin S, et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature 1998; 395: 137-43
31. Cock TA, Houten SM, Auwerx J. Peroxisome proliferator-activated receptor-γ: too much of a good thing causes harm. EMBO Rep 2004; 5: 142-7
32. Rocchi S, Picard F, Vamecq J, et al. A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol Cell 2001; 8: 737-47
33. Wang Y, Porter WW, Suh N, et al. A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ. Mol Endocrinol 2000; 14: 1550-6
34. Misra P, Chakrabarti R, Vikramadithyan RK, et al. PAT5A: a partial agonist of peroxisome proliferator-activated receptor γ is a potent antidiabetic thiazolidinedione yet weakly adipogenic. J Pharmacol Exp Ther 2003; 306: 763-71
35. Palakurthi SS, Aktas H, Grubissich LM, et al. Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor gamma and mediated by inhibition of translation initiation. Cancer Res 2001; 61: 6213-8
36. Chawla A, Barak Y, Nagy L, et al. PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001; 7: 48-52
37. Moore KJ, Rosen ED, Fitzgerald ML, et al. The role of PPAR-γ in macrophage differentiation and cholesterol uptake. Nat Med 2001; 7: 41-7
38. 2-induced apoptosis does not require PPARγ in breast cancer cells. J Lipid Res 2002; 43: 1818-28
39. Shiau CW, Yang CC, Kulp SK, et al. Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARγ. Cancer Res 2005; 65: 1561-9
40. Han S, Roman J. Rosiglitazone suppresses human lung carcinoma cell growth through PPARγ-dependent and PPARγ-independent signal pathways. Mol Cancer Ther 2006; 5: 430-7
41. Fukami MH, Salganicoff L. Human platelet storage organelles: a review. Thromb Haemost 1977; 38: 963-70
42. Harrison P, Cramer EM. Platelet alpha-granules. Blood Rev 1993; 7: 52-62
43. Denis MM, Tolley ND, Bunting M, et al. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 2005; 122: 379-91
44. Gnatenko DV, Dunn JJ, McCorkle SR, et al. Transcript profiling of human platelets using microarray and serial analysis of gene expression. Blood 2003; 101: 2285-93
45. Kieffer N, Guichard J, Farcet JP, et al. Biosynthesis of major platelet proteins in human blood platelets. Eur J Biochem 1987; 164: 189-95
46. Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-4
47. Chapelsky MC, Thompson-Culkin K, Miller AK, et al. Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin Pharmacol 2003; 43: 252-9
48. Thompson-Culkin K, Zussman B, Miller AK, et al. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res 2002; 30: 391-9
49. Bodary PF, Vargas FB, King SA, et al. Pioglitazone protects against thrombosis in a mouse model of obesity and insulin resistance. J Thromb Haemost 2005; 3: 2149-53
50. Li D, Chen K, Sinha N, et al. The effects of PPAR-γ ligand pioglitazone on platelet aggregation and arterial thrombus formation. Cardiovasc Res 2005; 65: 907-12
51. Haseruck N, Erl W, Pandey D, et al. The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors. Blood 2004; 103: 2585-92
52. Liu F, Morris S, Epps J, et al. Demonstration of an activation regulated NF-κB/I-κBα complex in human platelets. Thromb Res 2002; 106: 199-203
53. Gelman L, Michalik L, Desvergne B, et al. Kinase signaling cascades that modulate peroxisome proliferator-activated receptors. Curr Opin Cell Biol 2005; 17: 216-22
54. Pascual G, Fong AL, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ. Nature 2005; 437: 759-63
55. Ali FY, Davidson SJ, Moraes LA, et al. Role of nuclear receptor signaling in platelets: antithrombotic effects of PPARβ. Faseb J 2006; 20: 326-8
56. Barak Y, Nelson MC, Ong ES, et al. PPARγ is required for placental, cardiac, and adipose tissue development. Mol Cell 1999; 4: 585-95
57. Ryding AD, Sharp MG, Mullins JJ. Conditional transgenic technologies. J Endocrinol 2001; 171: 1-14
58. Setoguchi K, Misaki Y, Terauchi Y, et al. Peroxisome proliferator- activated receptor-γ haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis. J Clin Invest 2001; 108: 1667-75
59. Danese S, Fiocchi C. Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. Crit Rev Immunol 2005; 25: 103-21
60. Inwald DP, McDowall A, Peters MJ, et al. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ Res 2003; 92: 1041-8
61. Furman MI, Krueger LA, Linden MD, et al. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol 2004; 43: 2319-25
62. 2 production in human lung fibroblasts. J Immunol 1998; 160: 1053-7
63. Andre P, Nannizzi-Alaimo L, Prasad SK, et al. Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 2002; 106: 896-9
64. Elzey BD, Tian J, Jensen RJ, et al. Platelet-mediated modulation of adaptive immunity: a communication link between innate and adaptive immune compartments. Immunity 2003; 19: 9-19
65. Sempowski GD, Chess PR, Moretti AJ, et al. CD40 mediated activation of gingival and periodontal ligament fibroblasts. J Periodontol 1997; 68: 284-92
66. Sempowski GD, Chess PR, Phipps RP. CD40 is a functional activation antigen and B7-independent T cell costimulatory molecule on normal human lung fibroblasts. J Immunol 1997; 158: 4670-7
67. Quera R, Shanahan F. Thromboembolism -an important manifestation of inflammatory bowel disease. Am J Gastroenterol 2004; 99: 1971-3
68. Danese S, de la Motte C, Sturm A, et al. Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients. Gastroenterology 2003; 124: 1249-64
69. Danese S, Katz JA, Saibeni S, et al. Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients. Gut 2003; 52: 1435-41
70. Ludwiczek O, Kaser A, Tilg H. Plasma levels of soluble CD40 ligand are elevated in inflammatory bowel diseases. Int J Colorectal Dis 2003; 18: 142-7
71. Ghanim H, Garg R, Aljada A, et al. Suppression of nuclear factor-κB and stimulation of inhibitor κB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. J Clin Endocrinol Metab 2001; 86: 1306-12
72. Mohanty P, Aljada A, Ghanim H, et al. Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab 2004; 89: 2728-35
73. Vinik AI, Erbas T, Park TS, et al. Platelet dysfunction in type 2 diabetes. Diabetes Care 2001; 24: 1476-85
74. Almer LO, Nilsson IM. On fibrinolysis in diabetes mellitus. Acta Med Scand 1975; 198: 101-6
75. Imperatore G, Riccardi G, Iovine C, et al. Plasma fibrinogen: a new factor of the metabolic syndrome: a population-based study. Diabetes Care 1998; 21: 649-54
76. Betteridge DJ, El Tahir KE, Reckless JP, et al. Platelets from diabetic subjects show diminished sensitivity to prostacyclin. Eur J Clin Invest 1982; 12: 395-8
77. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991; 87: 432-8
78. Johnson M, Harrison HE, Raftery AT, et al. Vascular prostacyclin may be reduced in diabetes in man. Lancet 1979; 1: 325-6
79. Trovati M, Mularoni EM, Burzacca S, et al. Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients. Diabetes 1995; 44: 1318-22
80. Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest 1996; 98: 894-8
81. Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear nuclear factor κB and stimulates IκB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 2001; 86: 3257-65
82. Akai T, Naka K, Okuda K, et al. Decreased sensitivity of platelets to prostacyclin in patients with diabetes mellitus. Horm Metab Res 1983; 15: 523-6
83. Schafer A, Alp NJ, Cai S, et al. Reduced vascular NO bioavailability in diabetes increases platelet activation in vivo. Arterioscler Thromb Vasc Biol 2004; 24: 1720-6
84. Halushka PV, Rogers RC, Loadholt CB, et al. Increased platelet thromboxane synthesis in diabetes mellitus. J Lab Clin Med 1981; 97: 87-96
85. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004; 25: 4-7
86. Jinchuan Y, Zonggui W, Jinming C, et al. Upregulation of CD40-CD40 ligand system in patients with diabetes mellitus. Clin Chim Acta 2004; 339: 85-90
87. Varo N, Libby P, Nuzzo R, et al. Elevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products. Diab Vasc Dis Res 2005; 2: 81-7
88. Vaidyula VR, Rao AK, Mozzoli M, et al. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes 2006; 55: 202-8
89. Santilli F, Davi G, Consoli A, et al. Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus. J Am Coll Cardiol 2006; 47: 391-7
90. Loe H. Periodontal disease: the sixth complication of diabetes mellitus. Diabetes Care 1993; 16: 329-34
91. Genco RJ, Grossi SG, Ho A, et al. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. J Periodontol 2005; 76: 2075-84
92. Mackler BF, Waldrop TC, Schur P, et al. IgG subclasses in human periodontal disease. I. Distribution and incidence of IgG subclass bearing lymphocytes and plasma cells. J Periodontal Res 1978; 13: 109-19
93. Morton RS, Dongari-Bagtzoglou AI. Cyclooxygenase-2 is upregulated in inflamed gingival tissues. J Periodontol 2001; 72: 461-9
94. Offenbacher S, Salvi GE. Induction of prostaglandin release from macrophages by bacterial endotoxin. Clin Infect Dis 1999; 28: 505-13
95. Marx N, Imhof A, Froehlich J, et al. Effect of rosiglitazone treatment on soluble CD40L in patients with type 2 diabetes and coronary artery disease. Circulation 2003; 107: 1954-7
96. Varo N, Vicent D, Libby P, et al. Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones. Circulation 2003; 107: 2664-9
97. Sidhu JS, Cowan D, Tooze JA, et al. Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease. Am Heart J 2004; 147: e25
98. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-43
99. Lusis AJ. Atherosclerosis. Nature 2000; 407: 233-41
100. Ross R. Atherosclerosis -an inflammatory disease. N Engl J Med 1999; 340: 115-26
101. Gallino A, Haeberli A, Baur HR, et al. Fibrin formation and platelet aggregation in patients with severe coronary artery disease: relationship with the degree of myocardial ischemia. Circulation 1985; 72: 27-30
102. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-8
103. Ross R. The pathogenesis of atherosclerosis -an update. N Engl J Med 1986; 314: 488-500
104. Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 2003; 23: 2131-7
105. Badimon JJ, Zaman A, Helft G, et al. Acute coronary syndromes: pathophysiology and preventive priorities. Thromb Haemost 1999; 82: 997-1004
106. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 1992; 326: 242-50
107. Vorchheimer DA, Becker R. Platelets in atherothrombosis. Mayo Clin Proc 2006; 81: 59-68
108. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-84
109. Dong ZM, Chapman SM, Brown AA, et al. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest 1998; 102: 145-52
110. Huo Y, Schober A, Forlow SB, et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 9: 61-7
111. Langer H, May AE, Daub K, et al. Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro. Circ Res 2006; 98: e2-10
112. Andre P, Prasad KS, Denis CV, et al. CD40L stabilizes arterial thrombi by a β3 integrin-dependent mechanism. Nat Med 2002; 8: 247-52
113. Lutgens E, Gorelik L, Daemen MJ, et al. Requirement for CD154 in the progression of atherosclerosis. Nat Med 1999; 5: 1313-6
114. Mach F, Schonbeck U, Sukhova GK, et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A 1997; 94: 1931-6
115. Phipps RP. Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system. Proc Natl Acad Sci U S A 2000; 97: 6930-2
116. Aukrust P, Muller F, Ueland T, et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina: possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100: 614-20
117. Garlichs CD, Eskafi S, Raaz D, et al. Patients with acute coronary syndromes express enhanced CD40 ligand/CD154 on platelets. Heart 2001; 86 (6): 649-55
118. Garlichs CD, John S, Schmeisser A, et al. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation 2001; 104: 2395-400
119. Lee Y, Lee WH, Lee SC, et al. CD40L activation in circulating platelets in patients with acute coronary syndrome. Cardiology 1999; 92 (1): 11-6
120. Slupsky JR, Kalbas M, Willuweit A, et al. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost 1998; 80: 1008-14
121. Lutgens E, Cleutjens KB, Heeneman S, et al. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A 2000; 97: 7464-9
122. Sukhova GK, Schonbeck U, Rabkin E, et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 1999; 99: 2503-9
123. Schonbeck U, Sukhova GK, Shimizu K, et al. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A 2000; 97: 7458-63
124. Vishnevetsky D, Kiyanista VA, Gandhi PJ. CD40 ligand: a novel target in the fight against cardiovascular disease. Ann Pharmacother 2004; 38: 1500-8
125. Duval C, Chinetti G, Trottein F, et al. The role of PPARs in atherosclerosis. Trends Mol Med 2002; 8: 422-30
126. Lehrke M, Lazar MA. The many faces of PPARγ. Cell 2005; 123: 993-9
127. Wang M, Tafuri S. Modulation of PPARγ activity with pharmaceutical agents: treatment of insulin resistance and atherosclerosis. J Cell Biochem 2003; 89: 38-47
128. Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ. J Clin Invest 2004; 114: 1564-76
129. Samaha FF, Szapary PO, Iqbal N, et al. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol 2006; 26: 624-30
130. Azar RR, Kassab R, Zoghbi A, et al. Effects of clopidogrel on soluble CD40 ligand and on high-sensitivity C-reactive protein in patients with stable coronary artery disease. Am Heart J 2006; 151: 521e1-4
131. Xiao Z, Theroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol 2004; 43: 1982-8
132. Zondlo SC, Wang X, Feuerstein GZ. Effects of orally active glycoprotein IIb/IIIa antagonists on platelet CD40 ligand (CD154) expression and platelet-heteroaggregate formation. Thromb Res 2002; 106: 35-40