Different Effect of Statins on Platelet Oxidized-LDLReceptor (CD36 and LOX-1) Expressionin Hypercholesterolemic Subjects

Abstract

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions. Oxidized low-density lipoproteins (ox-LDL) are pro-atherogenic molecules and potent platelet agonists. CD36 and lectin-like ox-LDL receptor-1 (LOX-1) are specific ox-LDL receptors also expressed in platelets. This study was planned to address whether treatment with atorvastatin 10 mg/day, pravastatin 40 mg/day or simvastatin 20 mg/day could affect platelet CD36 and LOX-1 expression. Twenty-four patients for each treatment were evaluated after 3, 6, and 9 days and at 6 weeks for complete lipid profile (chromogenic), ox-LDL (ELISA), platelet P-selectin (P-sel), CD36, LOX-1 (FACS), and intracellular citrullin recovery (iCit) (HPLC). Data show hyperactivated platelets (P-sel absolute values, percent variation in activated cells, all p < 0.001), and CD36 and LOX-1 overexpression (all p < 0.001) in patients at baseline. P-sel, CD36, and LOX-1 were significantly decreased by atorvastatin and simvastatin (all p < 0.01) and related with iCit increase (r = 0.58,p < 0.001) and platelet-associated ox-LDL (r = 0.51, p < 0.01) at 9 days. Pravastatin reduced LOX-1 and P-sel (p < 0.05) at 6 weeks in relation with decreased LDL and ox-LDL (r = 0.39, p < 0.01 and r = 0.37, p < 0.01, respectively). These data suggest that atorvastatin and simvastatin reduce platelet activity by exposure of CD36 and LOX-1 before significant LDL reduction, whereas pravastatin action is detected later and in relation with LDL and ox-LDL lowering. Rapid and consistent reduction of CD36 and LOX-1 could be considered a direct anti-atherothrombotic mechanism related to the role of ox-LDL in platelet activation, platelet-endothelium interactions, and NO synthase activity.

Keywords

Statins Platelets ox-LDL CD36 LOX-1

References

Bolego C , Baetta R , Bellosta S , et al. Safety considerations for statins. Curr Opin Lipidol 2002;13:637.

Vaughan CJ , Gotto AM Jr , Basson CT . The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 1999;35:1.

Neaton JD , Blackburn H , Jacobs D. Serum cholesterol level and mortality findings for men screened in the multiple risk factor intervention trial. Arch Intern Med 1992;152:1490.

Comparato C , Altana C , Bellosta S , et al.

Clinically relevant pleiotropic effects of statins: Drug properties or effects of profound cholesterol reduction?

Nutr Metab Cardiovasc Dis 2001;11:328.

Fuster V , Badimon L , Badimon JJ , Chesebro JH . The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242.

Prisco D , Rogasi PG , Paniccia R , et al. Altered lipids composition and thromboxane A2 formation in platelets from patients affected by IIa hyperlipoproteinemia. Thromb Res 1988;50:593.

Nofer JR , Tepel M , Kehrel B , et al. Low-density lipoproteins inhibit the Na+/H+ antiport in human platelets. A novel mechanism of enhancing platelet activity in hyper-cholesterolemia. Circulation 1997;95:1370.

Chen LY , Metha P , Metha JL . Oxidized LDL decreases L-arginine uptake and nitric oxide syntase protein expression in human platelets. Relevance of the effect of oxidized LDL on platelet function. Circulation 1996;93:1740.

Zhao B , Dierichs R , Miller FN , Dean WL . Oxidized low density lipoprotein inhibits platelet plasma membrane Ca2+-ATPase. Cell Calcium 1996;19:453.

10.

Retzer M , Siess W , Essler M. Midly oxidized low density lipoprotein induces platelet shape change via Rho-kinasedepenent phosphorylation of myosin light chain and moesin. FEBS Lett 2000;446:70.

11.

Weidtmann A , Scheithe R , Hrboticky N , et al. Midly oxidized LDL induces platelet aggregation through activation of phospholipase A2. Arterioscler Thromb Vasc Biol 1995;15:1131.

12.

Puccetti L , Pasqui AL , Pastorelli M , et al. Time-dependent effect of statins on platelet function in hypercholesterolemic subjects. Eur J Clin Invest 2002;32:901.

13.

Sawamura T , Kume N , Aoyama T , et al. An endothelial receptor for oxidized low-density lipoprotein. Nature 1997;386:73.

14.

Moriwaki H , Kume N , Sawamura T , et al. Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipoprotein. Arterioscler Thromb Vasc Biol 1998;18:1541.

15.

Yoshida H , Kondratenko N , Green S. Identification of the lectin-like receptor of oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor. Biochem J 1998;334:9.

16.

Chen M , Kakutani M , Narudo T , et al. Activation-dependent surface expression of LOX-1 in human platelets. Biochem Biophys Res Commun 2001;282:153.

17.

Mehta JL , Li D. Identification, regulation and function of a novel lectin.like oxidized low-density lipoprotein receptor. J Am Coll Cardiol 2002;39:1429.

18.

Sakurai K , Sawamura T. Endothelial dysfunction via lectin-like oxidized low-density lipoprotein receptor-1: Close relationship with oxidative stress. J Pharmacol Sci 2003;91:182.

19.

Cominacini L , Fratta Pasini A , Garbin U , et al. The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells. J Am Coll Cardiol 2003;41:499.

20.

Metha JL , Li DY , Chen HJ , et al. Inhibition of LOX-1 by statins may relate to upregulation of eNOS. Biochem Biophys Res Commun 2001;289:857.

21.

Endemann G , Stanton LW , Maden KS , et al. CD36 is a receptor for oxidized low-density lipoprotein. J Biol Chem 1993;268:11811.

22.

Volf I , Moeslinger T , Cooper J , et al. H platelets exclusively bind oxidized low-density lipoprotein showing no specificity for acetylated low-density lipoprotein. FEBS Lett 1999;449:141.

23.

Takahashi Y , Fuda H , Yanai H , et al. Significance of membrane glycoproteins in platelet interaction with oxidized low-density lipoprotein. Semin Thromb Haemost 1998;24:251.

24.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults . Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation and treatment of high blood cholesterol in adults (adults treatment panel III). JAMA 2001;285:2486.

25.

Jones P , Kafonek S , Laurora I. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin and fluvastatin in patients with hypercholesterolemia (The CURVES study). Am J Cardiol 1998;81:582.

26.

Mustard JF , Kinlough-Rathbone RL , Packham MA . Isolation of human platelets from plasma by centrifugation and washing. Meth Enzymol 1989;169:3.

27.

Ferroni P , Speziale G , Ruvolo G , et al.

Platelet activation and cytokine production during hypothermic cardiopulmonary bypass. A possible correlation?

Thromb Haemost 1998;80:58.

28.

Clauss A. Rapid physiological coagulation method in determination of fibrinogen. Acta Haematol 1957;17:237.

29.

Araki A , Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatog 1987;422:43.

30.

Plana JC , Jones PH . The use of statins in acute coronary syndromes: the mechanisms behind the outcomes. Curr Atheroscler Rep 2001;3:355.

31.

Blann AD , Nadar SK , Lip GYH . The adesion molecule P-selectin and cardiovascular disease. Eur Heart J 2003;24:2166.

32.

Aoyama T , Fujiwara H , Masaki T , Sawamura T. Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophospha tidylcholine in cultured endothelial cells. J Mol Cell Cardiol 1999;31:2101.

33.

Metha JL , Li DY , Chen HJ , et al. Inhibition of LOX-1 by statins may relate to upregulation of eNOS. Biochem Biophys Res Commun 2001;289:857.

34.

Li DY , Chen HJ , Romeo F , et al. Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells: Role of LOX-1. J Pharmacol Exp Ther 2002;302:601.

35.

Li DY , Chen HJ , Metha JL . Statins inhibit oxidized-LDL-mediated LOX-1 expression, uptake of oxidized-LDL and reduction in PKB phpsphorylation. Cardiovasc Res 2001;52:5.

36.

Ziesennis S , Zahler S , Muller I , et al. Modified phosphatidylethanolamine as the active component of oxidized low density lipoprotein promoting platelet prothrombinase activity. J Biol Chem 2001;276:19828.

37.

Hartwich J , Dembinska-Kiec A , Gruca A , et al. Regulation of platelet adhesion by oxidized lipoproteins and oxidized phospholipids. Platelets 2002;13:141.

38.

Colli S , Eligini S , Lalli M , et al. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997;17:265.

39.

Jialal I , Stein D , Balis D , et al. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933.

40.

Holven KB , Scholz H , Halvorsen B , et al. Hyper-homocysteinemic subjects have enhanced expression of lectin-like oxidized LDL receptor-1 in mononuclear cells. J Nutr 2003;133:3588.

41.

Puccetti L , Pasqui AL , Pastorelli M , et al. 3’UTR/T polymorphism of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with modified anti-platelet activity of atorvastatin in hypercholesterolemic subjects. Atherosclerosis 2005 epub: April 22, 2005.