P2Y12 Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis
P2Y12 Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis
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P2Y(12) 在动脉粥样硬化形成过程中通过 Cofilin 去磷酸化促进血管平滑肌细胞迁移
DOI：
10.1161/atvbaha.116.308725
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Bo Hu
中科院分区：
文献类型：
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作者：
Xuan Niu;Shulan Pi;Suraj Baral;Yuanpeng Xia;Quanwei He;Yanan Li;HuiJuan Jin;Man Li;Mengdie Wang;Ling Mao;Bo Hu
目的p2y12是一种公认的在血小板上表达的受体，是噻吩吡啶类抗血小板药物的靶点。然而，最近的证据表明，在血管壁表达的p2y12在动脉粥样硬化中起作用，但其机制尚不清楚。在这项研究中，我们研究了血管壁p2y12如何介导血管平滑肌细胞（VSMCs）迁移并促进动脉粥样硬化进展的分子机制。方法与结果采用高脂饮食喂养的载脂蛋白e缺乏小鼠模型，我们发现VSMCs中p2y12的表达呈时间依赖性增加，并与斑块面积呈线性关系。此外，给予p2y12受体拮抗剂12周可显著减少动脉粥样硬化，降低斑块中VSMCs的丰度。在培养的VSMCs中，我们发现p2y12受体的激活可以抑制cAMP/蛋白激酶A信号通路，从而诱导cofilin去磷酸化和丝状肌动蛋白分解，从而增强VSMCs的运动性和迁移性。此外，接受氯吡格雷治疗的患者颈动脉斑块中p2y12阳性的VSMCs数量减少。结论血管壁p2y12受体通过cofilin去磷酸化促进VSMCs迁移，在动脉粥样硬化病变的发生发展中起关键作用，可能作为动脉粥样硬化的治疗靶点。
ObjectiveP2Y12is a well-recognized receptor expressed on platelets and the target of thienopyridine-type antiplatelet drugs. However, recent evidence suggests that P2Y12expressed in vessel wall plays a role in atherogenesis, but the mechanisms remain elusive. In this study, we examined the molecular mechanisms of how vessel wall P2Y12mediates vascular smooth muscle cells (VSMCs) migration and promotes the progression of atherosclerosis.Approach and ResultsUsing a high-fat diet–fed apolipoprotein E–deficient mice model, we found that the expression of P2Y12in VSMCs increased in a time-dependent manner and had a linear relationship with the plaque area. Moreover, administration of P2Y12receptor antagonist for 12 weeks caused significant reduction in atheroma and decreased the abundance of VSMCs in plaque. In cultured VSMCs, we found that activation of P2Y12receptor inhibited cAMP/protein kinase A signaling pathway, which induced cofilin dephosphorylation and filamentous actin disassembly, thereby enhancing VSMCs motility and migration. In addition, the number of P2Y12-positive VSMCs was decreased in the carotid artery plaque from patients receiving clopidogrel.ConclusionsVessel wall P2Y12receptor, which promotes VSMCs migration through cofilin dephosphorylation, plays a critical role in the development of atherosclerotic lesion and may be used as a therapeutic target for atherosclerosis.