Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a non-coding RNA. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of atherosclerosis which causes CAD. We ascertained whether 9p21 genotype had an influence on CDKN2A/CDKN2B/ANRIL expression levels in VSMCs, VSMC proliferation and VSMC content in atherosclerotic plaques. Immunohistochemical examination showed that VSMCs in atherosclerotic lesions expressed p16(INK4a), p14(ARF) and p15(INK4b). Analyses of primary cultures of VSMCs showed that the 9p21 risk genotype was associated with reduced expression of p16(INK4a), p15(INK4b) and ANRIL (P = 1.2 × 10(-5), 1.4 × 10(-2) and 3.1 × 10(-9)) and with increased VSMC proliferation (P = 1.6 × 10(-2)). Immunohistochemical analyses of atherosclerotic plaques revealed an association of the risk genotype with reduced p15(INK4b) levels in VSMCs (P = 3.7 × 10(-2)) and higher VSMC content (P = 5.6 × 10(-4)) in plaques. The results of this study indicate that the 9p21 variation has an impact on CDKN2A and CDKN2B expression in VSMCs and influences VMSC proliferation, which likely represents an important mechanism for the association between this genetic locus and susceptibility to CAD.
Objectives-Statins and fibrates are hypolipidemic drugs which decrease cardiac events in individuals without raised levels of cholesterol. These drugs inhibit platelet function, but the mechanisms by which this pleiotropic effect is exerted are not known. Methods and Results-We used a range of approaches to show statins inhibit human platelet activation in vitro while engaging PPAR␣ and PPAR␥. The effects of simvastatin were prevented by the PPAR␥ antagonist GW9662 or the PPAR␣ antagonist GW6471. In a small-scale human study fluvastatin activated PPAR␣ and PPAR␥ in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPAR␣ antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPAR␣ Ϫ/Ϫ mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPAR␣ in murine platelets. PKC␣, which influences platelet activation, associated and immune-precipitated with PPAR␥ in platelets stimulated with statins and with PPAR␣ in platelets stimulated with fenofibrate. Conclusions-This study is the first to provide a unifying explanation of how fibrates and statins reduce thrombotic and cardiovascular risk. Our findings that PPARs associate with PKC␣ in platelets also provide a mechanism by which these effects are mediated. Key Words: platelets Ⅲ statin Ⅲ fibrate Ⅲ PPAR␣, PPAR␥ S tatins are widely prescribed cholesterol-lowering drugs that are first-line treatments for the prevention of coronary artery disease and atherosclerosis, reducing the incidence of thrombotic events such as heart attack and stroke. 1 Statins inhibit the activity of a key enzyme in cholesterol synthesis within the body, 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and so reduce cholesterol formation. 2 Statins are classified as natural (eg, pravastatin), synthetic (eg, fluvastatin), or semisynthetic (eg, simvastatin). Like the statins, the fibrates are widely used See accompanying article on page 620lipid-lowering drugs that reduce the incidence of heart attack and stroke. [3][4][5] Fibrates reduce triglycerides and increase high-density lipoprotein cholesterol. Importantly, statins and fibrates are preventative against heart attack and stroke, even in individuals with normal levels of circulating cholesterol. 1,2,6 However, the mechanisms by which statins or fibrates cause these noncholesterol related, or pleiotropic, protective effects are not completely understood.Interestingly both statins and fibrates inhibit platelet function, 3,7 which is, of course, a widely recognized property of drugs such as aspirin and clopidogrel that are used to reduce the incidence of heart attacks and strokes. 6,8 However, the mechanisms by which statins and fibrates inhibit platelets are unclear. It is not known whether they are a consequence of lowering cholesterol or mediated via some other mechanism. 1,3,9 Here we show that statins and fibrates have rapid and direct inhibitory effects on platelet function ...
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