Zhang Yong, Qin Wei, Zhang Longyin, Wu Xianxian, Du Ning, Hu Yingying, Li Xiaoguang, Shen Nannan, Xiao Dan, Zhang Haiying, Li Zhange, Zhang Yue, Yang Huan, Gao Feng, Du Zhimin, Xu Chaoqian, Yang Baofeng
1] Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150081, China [2] Institute of Cardiovascular Research, Harbin Medical University, Harbin 150081, China.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150081, China.
Sci Rep. 2015 Mar 24;5:9401. doi: 10.1038/srep09401.
Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR-26a expression was substantially reduced in the aortic intima of ApoE(-/-) mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a, and TRPC6 overexpression abolished the anti-apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR-26a for atherosclerosis associated with apoptotic cell death.
动脉粥样硬化是一种慢性炎症性疾病，是心肌梗死和中风等危及生命并发症的主要原因。内皮细胞凋亡在动脉粥样硬化病变的发生和发展中起着至关重要的作用。尽管已鉴定出一部分微小RNA（miR）是动脉粥样硬化的关键调节因子，但关于它们参与动脉粥样硬化中内皮细胞凋亡的研究仍然有限。在我们的研究中，我们发现，喂食高脂饮食（HFD）的ApoE（-/-）小鼠的主动脉内膜中miR-26a表达显著降低。用氧化低密度脂蛋白（ox-LDL）处理人主动脉内皮细胞（HAEC）可抑制miR-26a表达。MTT试验和TUNEL染色结果证明，强制表达miR-26a可抑制内皮细胞凋亡。进一步分析确定瞬时受体电位阳离子通道蛋白6（TRPC6）是miR-26a的一个靶标，TRPC6过表达消除了miR-26a的抗凋亡作用。此外，发现胞质钙和线粒体凋亡途径介导了miR-26a对内皮细胞凋亡的有益作用。综上所述，我们的研究揭示了miR-26a在内皮细胞凋亡中的新作用，并表明miR-26a对与凋亡性细胞死亡相关的动脉粥样硬化具有治疗潜力。
