自噬在血管紧张素II诱导的动脉粥样硬化中的作用及机制

项目名称： 自噬在血管紧张素II诱导的动脉粥样硬化中的作用及机制

项目编号： No.81470563

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张国兴

作者单位： 苏州大学

项目金额： 73万元

中文摘要： 动脉粥样硬化是引发心血管疾病的主要原因之一。大量的报道证实血管紧张素II（Ang II）在动脉粥样硬化中起着重要的作用，机制包括升高血压，诱导活性氧的大量释放，损伤内皮细胞，诱发炎症，促进血管平滑肌细胞迁移，增殖，凋亡，从而使血管发生动脉粥样硬化。细胞自噬传统地被认为具有保护细胞的作用，然而过度的自噬可引起细胞死亡。自噬可经多种途径激活，其中之一是可被活性氧激活。因此，本课题的假说是Ang II可通过激活NADPH氧化酶和线粒体KATP通道开放导致产生大量活性氧，诱导细胞自噬，从而导致细胞损伤，参与动脉粥样硬化的发生和发展。课题将分别在离体血管平滑肌和内皮细胞及在体小鼠（ApoE-/-)上，证明Ang II可诱导血管细胞自噬，同时应用AT1受体拮抗剂，NADPH氧化酶、线粒体KATP通道抑制剂及自噬水平的各种抑制，证明本假说的正确性，为临床抗动脉粥样硬化提供实验依据和新靶点。

中文关键词： 动脉粥样硬化；自噬；血管紧张素II；活性氧；线粒体ATP敏感性钾通道

英文摘要： Atherosclerosis is one of the important causes for cardiovascular diseases. Angiotensin II (Ang II) has been demonstrated play an essential role in the development of atherosclerosis, involved mechanisms including elevation of blood pressure, increase of reactive oxygen species (ROS) production, endothelial cell injury, induction of inflammation, induction of vascular smooth muscle cells' (VSMCs) migration, proliferation and apoptosis, thereafter, resulting in the development of atherosclerosis. Autophagy is traditionally regarded plays a protective role for cell survival, however, higher degree of autophagy could lead cell death. Several pathways has been demonstrated to activate autophagy, one is through increase of ROS production. Ang II has been demonstrated to increase ROS production via NADPH oxidase and mitochondrial KATP channel, consequently induces cell autophagy, leading to cell injury and death, involving in the pathogenesis of atherosclerosis. The present study is designed to demonstrate that Ang II could induce vascular cell autophagy using VSMCs, endothelial cells and ApoE knock-out mouse administrated with Ang II. At the same time, AT1 receptor antagonist, NADPH oxidase, KATP channel, autophagy inhibitors are pretreated to elucidate the possible involvement of autophagy in the development of atherosclerosis, and possible mechanisms involved in. The present study will provide novel basic evidence and target for clinical anti-atherosclerosis therapy.

英文关键词： atherosclerosis;autophagy;angiotensin II;reactive oxygen species;mitochondrial KATP channel