Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou.
State Key Laboratory of Diagnosis and Treatment for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou.
Haematologica. 2022 Jun 1;107(6):1358-1373. doi: 10.3324/haematol.2021.279770.
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 PPARa 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.
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密切相关。过氧化物酶体增殖物激活受体α（PPARα）是脂质代谢的重要调节因子。它被认为同时影响血栓形成和止血，但潜在机制尚不清楚。在这项研究中，研究了 PPARα 在与血脂异常相关的血小板激活和血栓形成中的作用和机制。利用 PPARα 缺失（Pparα-/-）的小鼠，我们证明了 PPARa 是血小板激活和血栓形成所必需的。PPARα 的作用严重依赖于血小板致密颗粒的分泌，并通过 p38MAPK/Akt、脂肪酸β氧化和 NAD（P）H 氧化酶途径贡献。重要的是，PPARα 及其相关途径介导了高脂肪饮食诱导的促血栓形成状态和氧化型低密度脂蛋白引起的血小板高反应性。血小板反应性与 PPARα 的表达水平呈正相关，这一点从野生型、嵌合型（Pparα+/-）和 Pparα-/-小鼠的数据中得到了证实。在高脂血症患者的血小板中也重现了这种正相关。在脂质处理的巨核细胞系中，发现脂质诱导的活性氧-NF-kB 途径上调了高脂血症中血小板的 PPARα。这些数据表明，血小板 PPARα 对血小板激活具有重要的调节作用，并有助于高血脂状态下的促血栓形成状态。
