Mdivi-1, a mitochondrial fission inhibitor, reduces angiotensin-II- induced hypertension by mediating VSMC phenotypic switch
Mdivi-1, a mitochondrial fission inhibitor, reduces angiotensin-II- induced hypertension by mediating VSMC phenotypic switch
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Mdivi-1 是一种线粒体裂变抑制剂，通过介导 VSMC 表型转换来降低血管紧张素 II 诱导的高血压
DOI：
10.1016/j.biopha.2021.111689
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发表时间：
2021-05-15
影响因子：
7.5
通讯作者：
Cai, Jun
中科院分区：
文献类型：
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作者：
Deng, Yue;Li, Shuangyue;Cai, Jun
血管平滑肌细胞（VSMC）表型转换在高血压的发病机制中起重要作用。线粒体动力学，如线粒体分裂，也可以有助于VSMC表型转换。线粒体分裂是否可以作为抗高血压药物开发的新靶点仍不清楚。在本研究中，我们证实，血管紧张素II（AngII）迅速，持续诱导VSMCs线粒体分裂。同时检测了线粒体分裂关键蛋白动力蛋白相关蛋白1（dynamin-related protein-1，Drp 1）Ser 616位点的磷酸化状态，并观察了血管紧张素II诱导的高血压小鼠血管平滑肌细胞和动脉中Drp 1的线粒体转位。Drp 1抑制剂线粒体分裂抑制剂-1（Mdivi-1）显著逆转AngII诱导的Drp 1磷酸化、线粒体分裂和活性氧化物质生成。用Mdivi-1（20 mg/kg/每隔一天）治疗显著减弱AngII诱导的高血压（22 mmHg）、动脉重塑和心脏肥大，部分是通过防止VSMC表型转换。此外，Mdivi-1治疗与肝或肾功能损伤无关。总的来说，这些结果表明，Mdivi-1抑制线粒体分裂，恢复线粒体活性，并防止血管紧张素II诱导的VSMC表型转换，导致降低高血压。
Vascular smooth muscle cell (VSMC) phenotypic switch plays an essential role in the pathogenesis of hypertension. Mitochondrial dynamics, such as mitochondrial fission, can also contribute to VSMC phenotypic switch. Whether mitochondrial fission act as a novel target for anti-hypertensive drug development remains unknown. In the present study, we confirmed that angiotensin II (AngII) rapidly and continuously induced mitochondrial fission in VSMCs. We also detected the phosphorylation status of dynamin-related protein-1 (Drp1), a key protein involved in mitochondrial fission, at Ser616 site; and observed Drp1 mitochondrial translocation in VSMCs or arteries of AngII-induced hypertensive mice. The Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) dramatically reversed AngII-induced Drp1 phosphorylation, mitochondrial fission, and reactive oxidative species generation. Treatment with Mdivi-1 (20 mg/kg/every other day) significantly attenuated AngII-induced hypertension (22 mmHg), arterial remodeling, and cardiac hypertrophy, in part by preventing VSMC phenotypic switch. In addition, Mdivi-1 treatment was not associated with liver or renal functional injury. Collectively, these results indicate that Mdivi-1 inhibited mitochondrial fission, recovered mitochondrial activity, and prevented AngII-induced VSMC phenotypic switch, resulting in reduced hypertension.