The endothelium lines the luminal surface of every blood vessel, allowing it contact with circulating blood elements, as well as the underlying vascular smooth muscle layer. In healthy vessels, the endothelium expresses constitutive forms of nitric oxide synthase (NOSIII) and cyclo-oxygenase (COX-1), which produce the vasoactive hormones NO and prostacyclin, respectively. Both NO and prostacyclin relax blood vessels and inhibit platelet activation. The actions of prostacyclin are mediated by cell surface prostacyclin (IP) receptors and/or intracellular peroxisome proliferator-activated receptors (PPAR)β. The actions of NO are mediated predominately by activation of intracellular guanylyl cyclase, leading to the formation of cGMP. In platelets, the actions of NO and prostacyclin are synergistic, but in vessels their actions are additive. In diseased vessels, inducible forms of NOS (NOSII) and cyclo-oxygeanse (COX-2) are expressed in vascular smooth muscle, resulting in the release of large amounts of NO, prostacyclin and prostaglandin E 2 . The relative contribution of NOSII and COX-2 to vascular inflammation is still debated, but is likely to result in both protective and damaging responses. The relative contribution of constitutive forms of NOS and COX, as well as interactions between IP, PPARβ and guanylyl cyclase pathways in vessels and platelets, is discussed.
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 ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.