Aims Platelets participate in atherogenesis with mechanisms not yet fully clarified. Vascular wall MMP-2 is involved in the arterial remodelling accompanying atherosclerosis. Platelets contain and release MMP-2 but no informations are available on its role in atherosclerotic lesion formation. Methods and results We generated double knockout mice lacking the LDL receptor and MMP-2 only in circulating blood cells showing that they develop significantly lesser femoral intima thickening after photochemical-induced arterial damage and atherosclerotic lesions in the aorta, measured by the en face method, after 4 months of atherogenic diet. Moreover, repeated transfusions of autologous-activated platelets in LDLR−/− mice on atherogenic diet significantly enhanced the extension of aortic atherosclerotic lesions while transfusion of activated platelets from MMP-2−/− mice did not. In vitro coincubation studies showed that platelet-derived MMP-2 plays a pivotal role in the development and progression of atherosclerosis through a complex cross-talk between activated platelets, monocyte/macrophages, and endothelial cells. Translational studies in patients with CAD and chronic HIV infection showed that platelet surface expression of MMP-2 highly significantly correlated with the degree of carotid artery stenosis. Conclusion We show a previously unknown mechanism of the pathway through which platelets expressing MMP-2 trigger the initial phases of atherosclerosis and provide a mechanism showing that they activate endothelial PAR-1 triggering endothelial p38MAPK signalling and the expression of adhesion molecules. The development of drugs blocking selectively platelet MMP-2 or its expression may represent a new approach to the prevention of atherosclerosis.

中文翻译：

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活化血小板上的基质金属蛋白酶 2 触发内皮 PAR-1 引发动脉粥样硬化

目的 血小板参与动脉粥样硬化形成的机制尚未完全阐明。血管壁 MMP-2 参与伴随动脉粥样硬化的动脉重塑。血小板含有并释放 MMP-2，但没有关于其在动脉粥样硬化病变形成中的作用的信息。方法和结果 我们产生了仅在循环血细胞中缺乏 LDL 受体和 MMP-2 的双敲除小鼠，表明它们在光化学诱导的动脉损伤和主动脉中的动脉粥样硬化病变后发生显着较少的股骨内膜增厚，通过 en face 方法测量，经过 4 个月的致动脉粥样硬化饮食。而且，在致动脉粥样硬化饮食的 LDLR-/- 小鼠中反复输注自体活化血小板显着增强了主动脉粥样硬化病变的扩展，而输注来自 MMP-2-/- 小鼠的活化血小板则没有。体外共孵育研究表明，血小板衍生的 MMP-2 通过活化的血小板、单核细胞/巨噬细胞和内皮细胞之间的复杂交互作用，在动脉粥样硬化的发展和进展中起关键作用。对 CAD 和慢性 HIV 感染患者的转化研究表明，血小板表面 MMP-2 的表达与颈动脉狭窄程度高度显着相关。结论 我们展示了表达 MMP-2 的血小板触发动脉粥样硬化初始阶段的途径的先前未知机制，并提供了一种机制表明它们激活内皮 PAR-1 触发内皮 p38MAPK 信号传导和粘附分子的表达。开发选择性阻断血小板 MMP-2 或其表达的药物可能代表了一种预防动脉粥样硬化的新方法。