Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs
Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs
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DOI：
10.1161/atvbaha.108.183160
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发表时间：
2009-05-01
影响因子：
8.7
通讯作者：
Warner, Timothy D.
中科院分区：
文献类型：
--
作者：
Ali, Ferhana Y.;Armstrong, Paul C. J.;Warner, Timothy D.
目的：他汀类和贝特类是降血脂药物，可降低胆固醇水平不升高的个体的心脏事件。这些药物抑制血小板的功能，但这种多效性的作用是发挥的机制是unknow.Methods和Results-We使用了一系列的方法来显示他汀类药物抑制人血小板在体外活化，同时从事过氧化物酶体增殖物激活受体α和过氧化物酶体增殖物激活受体γ。辛伐他汀的作用被PPAR γ拮抗剂GW 9662或PPAR α拮抗剂GW 6471阻止。在一项小规模的人体研究中，氟伐他汀激活了血小板中的PPAR α和PPAR γ，并减少了对花生四烯酸体外反应的聚集。GW 6471的PPAR α拮抗作用阻止了非诺贝特的作用。非诺贝特增加了野生型小鼠的出血时间，但在PPAR α（-/-）小鼠中没有。非诺贝特而非辛伐他汀对血小板聚集的抑制作用可通过小鼠血小板中PPAR α的缺失来阻止。PKC α，这影响血小板活化，相关和免疫沉淀与他汀类药物刺激血小板和血小板刺激与非诺贝特. Conclusions-这项研究是第一个提供一个统一的解释如何贝特类药物和他汀类药物降低血栓形成和心血管风险。我们的发现，PPARs与血小板中的PKC α相关，也提供了介导这些作用的机制。（Arterioscler Thromb Vasc Biol.2009; 29：706-711.）
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 alpha and PPAR gamma. The effects of simvastatin were prevented by the PPAR gamma antagonist GW9662 or the PPAR alpha antagonist GW6471. In a small-scale human study fluvastatin activated PPAR alpha and PPAR gamma in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPAR alpha antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPAR alpha(-/-) mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPAR alpha in murine platelets. PKC alpha, which influences platelet activation, associated and immune-precipitated with PPAR gamma in platelets stimulated with statins and with PPAR alpha 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 alpha in platelets also provide a mechanism by which these effects are mediated. (Arterioscler Thromb Vasc Biol. 2009; 29: 706-711.)