Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Leibniz Institut für Analytische Wissenschaften - ISAS- e.V, Dortmund, Germany.
Sci Rep. 2020 Dec 8;10(1):21407. doi: 10.1038/s41598-020-78522-9.
Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in Apoe and Ldlr mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (Apoe mice). Bone marrow from wild-type or Ldlr mice was transplanted into irradiated Ldlr recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in Apoe and Ldlr mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype.
高脂血症是心血管疾病的一个明确的危险因素。全世界数以百万计的人表现出与饮食和生活方式相关的轻度血浆脂质和胆固醇升高。虽然严重高脂血症的促血栓形成风险已经确立，但中度高脂血症的影响尚不清楚。在这里，我们研究了喂食正常饮食的 Apoe 和 Ldlr 小鼠中的血小板活化和动脉血栓形成，导致血浆胆固醇轻度升高。在两种敲除小鼠的血液中，胶原依赖性血栓和纤维蛋白形成在流动下增强。这些作用在年龄较大的小鼠的严重高脂血症血液中以及在喂食高脂肪饮食（Apoe 小鼠）时并没有增加。来自野生型或 Ldlr 小鼠的骨髓被移植到辐射照射的 Ldlr 受体中。值得注意的是，嵌合小鼠的血液中的血栓形成增强，表明高脂血症环境改变了野生型血小板，而不是遗传修饰。血小板蛋白质组揭示了三种基因型之间的高度相似性，没有明确表明存在基于共同蛋白质的功能获得。血小板脂质组揭示了轻度高脂血症小鼠中脂质谱的改变。总之，在 Apoe 和 Ldlr 小鼠中，血浆和血小板胆固醇的适度升高增加了血小板在血栓形成和随后的纤维蛋白形成中的反应性，导致血栓形成表型。
