Wu Nan, Zheng Fen, Li Na, Han Ying, Xiong Xiao-Qing, Wang Jue-Jin, Chen Qi, Li Yue-Hua, Zhu Guo-Qing, Zhou Ye-Bo
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, 211166, China.
Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, China.
Redox Biol. 2021 Dec 6;48:102204. doi: 10.1016/j.redox.2021.102204.
Superoxide and vascular smooth muscle cells (VSMCs) migration and proliferation play crucial roles in the vascular remodeling. Vascular remodeling contributes to the development and complications of hypertension. Rho family GTPase 3 (RND3 or RhoE), an atypical small Rho-GTPase, is known to be involved in cancer development and metastasis. However, the roles of RND3 in superoxide production and cardiovascular remodeling are unknown. Here, we uncovered the critical roles of RND3 in attenuating superoxide production, VSMCs migration and proliferation, and vascular remodeling in hypertension and its underline mechanisms. VSMCs were isolated and prepared from thoracic aorta of Male Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR). RND3 mRNA and protein expressions in arteries and VSMCs were down-regulated in SHR. RND3 overexpression in VSMCs reduced NAD(P)H oxidase (NOX) activity, NOX1 and NOX2 expressions, mitochondria superoxide generation, and HO production in SHR. Moreover, the RND3 overexpression inhibited VSMCs migration and proliferation in SHR, which were similar to the effects of NOX1 inhibitor ML171 plus NOX2 inhibitor GSK2795039. Rho-associated kinase 1 (ROCK1) and RhoA expressions and myosin phosphatase targeting protein 1 (MYPT1) phosphorylation in VSMCs were increased in SHR, which were prevented by RND3 overexpression. ROCK1 overexpression promoted NOX1 and NOX2 expressions, superoxide and HO production, VSMCs migration and proliferation in both WKY and SHR, which were attenuated by RND3 overexpression. Adenoviral-mediated RND3 overexpression in SHR attenuated hypertension, vascular remodeling and oxidative stress. These results indicate that RND3 attenuates VSMCs migration and proliferation, hypertension and vascular remodeling in SHR via inhibiting ROCK1-NOX1/2 and mitochondria superoxide signaling.
超氧化物以及血管平滑肌细胞（VSMCs）的迁移和增殖在血管重塑过程中发挥着关键作用。血管重塑会导致高血压的发展及其并发症。Rho家族GTP酶3（RND3或RhoE），一种非典型的小Rho - GTP酶，已知参与癌症的发展和转移。然而，RND3在超氧化物产生和心血管重塑中的作用尚不清楚。在此，我们揭示了RND3在减轻高血压中超氧化物产生、VSMCs迁移和增殖以及血管重塑方面的关键作用及其潜在机制。从雄性Wistar - Kyoto大鼠（WKY）和自发性高血压大鼠（SHR）的胸主动脉中分离并制备VSMCs。SHR中动脉和VSMCs的RND3 mRNA和蛋白表达下调。VSMCs中RND3的过表达降低了SHR中NAD(P)H氧化酶（NOX）活性、NOX1和NOX2表达、线粒体超氧化物生成以及HO产生。此外，RND3过表达抑制了SHR中VSMCs的迁移和增殖，这与NOX1抑制剂ML171加NOX2抑制剂GSK2795039的作用相似。SHR中VSMCs的Rho相关激酶1（ROCK1）和RhoA表达以及肌球蛋白磷酸酶靶向蛋白1（MYPT1）磷酸化增加，而RND3过表达可阻止这种增加。ROCK1过表达促进了WKY和SHR中NOX1和NOX2表达、超氧化物和HO产生、VSMCs迁移和增殖，而RND3过表达则减弱了这些作用。腺病毒介导的SHR中RND3过表达减轻了高血压、血管重塑和氧化应激。这些结果表明，RND3通过抑制ROCK1 - NOX1/2和线粒体超氧化物信号传导，减轻了SHR中VSMCs的迁移和增殖、高血压以及血管重塑。
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