Ali Ferhana Y, Armstrong Paul C J, Dhanji Al-Rehan A, Tucker Arthur T, Paul-Clark Mark J, Mitchell Jane A, Warner Timothy D
Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, London, UK.
Arterioscler Thromb Vasc Biol. 2009 May;29(5):706-11. doi: 10.1161/ATVBAHA.108.183160. Epub 2009 Jan 15.
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.
We used a range of approaches to show statins inhibit human platelet activation in vitro while engaging PPARalpha and PPARgamma. The effects of simvastatin were prevented by the PPARgamma antagonist GW9662 or the PPARalpha antagonist GW6471. In a small-scale human study fluvastatin activated PPARalpha and PPARgamma in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPARalpha antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPARalpha-/- mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPARalpha in murine platelets. PKCalpha, which influences platelet activation, associated and immune-precipitated with PPARgamma in platelets stimulated with statins and with PPARalpha in platelets stimulated with fenofibrate.
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 PKCalpha in platelets also provide a mechanism by which these effects are mediated.
他汀类药物和贝特类药物是降血脂药物，可降低胆固醇水平未升高个体的心脏事件发生率。这些药物抑制血小板功能，但其发挥这种多效性作用的机制尚不清楚。
我们采用了一系列方法来表明他汀类药物在体外通过激活过氧化物酶体增殖物激活受体α（PPARα）和过氧化物酶体增殖物激活受体γ（PPARγ）来抑制人血小板活化。辛伐他汀的作用可被PPARγ拮抗剂GW9662或PPARα拮抗剂GW6471阻断。在一项小规模人体研究中，氟伐他汀激活血小板中的PPARα和PPARγ，并在体外降低花生四烯酸诱导的血小板聚集。GW6471拮抗PPARα可阻断非诺贝特的作用。非诺贝特可延长野生型小鼠的出血时间，但对PPARα基因敲除小鼠无效。在小鼠血小板中敲除PPARα可阻断非诺贝特（而非辛伐他汀）对血小板聚集的抑制作用。蛋白激酶Cα（PKCα）影响血小板活化，在用他汀类药物刺激的血小板中与PPARγ结合并发生免疫沉淀，在用非诺贝特刺激的血小板中与PPARα结合并发生免疫沉淀。
本研究首次对贝特类药物和他汀类药物如何降低血栓形成和心血管风险提供了统一的解释。我们发现血小板中的PPARs与PKCα相关，这也为这些作用的介导提供了一种机制。
