Critical role of peroxisome proliferator-activated receptor α in promoting platelet hyperreactivity and thrombosis under hyperlipidemia.
Critical role of peroxisome proliferator-activated receptor α in promoting platelet hyperreactivity and thrombosis under hyperlipidemia.
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过氧化物酶体增殖物激活受体α在高脂血症下促进血小板高反应性和血栓形成中的关键作用
DOI：
10.3324/haematol.2021.279770
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发表时间：
2022-06-01
期刊：
影响因子：
10.1
通讯作者：
Hu, Hu
中科院分区：
文献类型：
--
作者：
Li, Li;Zhou, Jiawei;Wang, Shuai;Jiang, Lei;Chen, Xiaoyan;Zhou, Yangfan;Li, Jingke;Shi, Jingqi;Liu, Pu;Shu, Zheyue;Gonzalez, Frank J.;Liu, Aiming;Hu, Hu
血小板高反应性和动脉粥样硬化血栓形成风险增加与血脂异常有关。过氧化物酶体增殖物激活受体α(PPARα)是脂代谢的重要调节因子。它被认为同时影响血栓形成和止血，但其潜在的机制还不是很清楚。本研究旨在探讨PPARα在与血脂异常相关的血小板活化和血栓形成中的作用和机制。利用PPARα缺失的小鼠(PPARα-/-)，我们证明了PPARα是血小板激活和血栓形成所必需的。PPARα的作用依赖于血小板致密颗粒的分泌，并通过p38MAPK/AKT、脂肪酸b氧化和NAD(P)H氧化酶途径发挥作用。重要的是，PPARα及其相关途径介导了高脂饮食诱导的血栓前状态和氧化低密度脂蛋白引起的血小板过度活动。来自野生型、嵌合型(PPARα+/-)和PPARα-/-小鼠的数据显示，血小板反应性与PPARα的表达水平呈正相关。这种正相关性在高脂血症患者的血小板中得到了重现。在脂质处理的巨核细胞系中，脂质诱导的活性氧-核因子-kB途径被发现在高脂血症中上调血小板PPARα。这些数据表明，血小板PPARα在高脂血症下的血栓前状态中起着重要的调节作用。
Platelet hyperreactivity and increased atherothrombotic risk are specifically associated with dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARα) is an important regulator of lipid metabolism. It has been suggested to affect both thrombosis and hemostasis, yet the underlying mechanisms are not well understood. In this study, the role and mechanism of PPARα in platelet activation and thrombosis related to dyslipidemia were examined. Employing mice with deletion of PPARα (Pparα-/-), we demonstrated that PPARα is required for platelet activation and thrombus formation. The effect of PPARα is critically dependent on platelet dense granule secretion, and is contributed by p38MAPK/Akt, fatty acid b-oxidation, and NAD(P)H oxidase pathways. Importantly, PPARα and the associated pathways mediated a prothrombotic state induced by a high-fat diet and platelet hyperactivity provoked by oxidized low density lipoproteins. Platelet reactivity was positively correlated with the levels of expression of PPARα, as revealed by data from wild-type, chimeric (Pparα+/-), and Pparα-/- mice. This positive correlation was recapitulated in platelets from hyperlipidemic patients. In a lipid-treated megakaryocytic cell line, the lipid-induced reactive oxygen species-NF-kB pathway was revealed to upregulate platelet PPARα in hyperlipidemia. These data suggest that platelet PPARα critically mediates platelet activation and contributes to the prothrombotic status under hyperlipidemia.
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影响因子：
4.8
作者：
Ali, Ferhana Y.;Davidson, Simon J.;Mitchell, Jane A.
通讯作者：
Mitchell, Jane A.
DOI：
10.1161/atvbaha.108.183160
发表时间：
2009-05-01
影响因子：
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作者：
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通讯作者：
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10.4
作者：
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通讯作者：
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影响因子：
7.4
作者：
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通讯作者：
Williams, Mark S.
DOI：
10.1161/01.atv.0000158381.02640.4b
发表时间：
2005-04-01
影响因子：
8.7
作者：
Korporaal, SJA;Gorter, G;Akkerman, JWN
通讯作者：
Akkerman, JWN