线粒体分裂
安普克
细胞生物学
炎症体
NADPH氧化酶
氧化应激
磷酸化
AMP活化蛋白激酶
MFN1型
信号转导
基因敲除
化学
线粒体ROS
生物
蛋白激酶A
线粒体
细胞凋亡
活性氧
生物化学
线粒体融合
受体
线粒体DNA
基因
作者
Yang Li,Zhenhua Zhou,Meihong Chen,Jie Yang,Jing Leng,Guoquan Cao,Gui-Zhong Xin,Lifang Liu,Junping Kou,Baolin Liu,Ping Li,Xin Wen
标识
DOI:10.1089/ars.2015.6479
摘要
Aims: Corosolic acid (CRA) is a natural triterpenoid with antioxidative activity. This study was designed to elucidate the mechanism through which CRA protected vessel endothelial homeostasis by combating oxidative stress. Results: In endothelial cells, CRA induced dynamin-related protein 1 (Drp1) phosphorylation at Ser637 and thus inhibited mitochondrial fission in response to oxidative stress. It promoted AMP-activated protein kinase (AMPK) activity in an LKB1-dependent manner, and silencing AMPK abrogated its inhibitory effect on Drp1 activation and mitochondrial fission. CRA inhibited the translocation of p47phox and p67phox and the overexpression of gp91phox induced by palmitate (PA), demonstrating its action in suppression of NOX2 activation. Drp1 knockdown reduced PA-induced gp91phox expression, while Drp1 induction was also diminished by gp91phox knockdown, suggesting the reciprocal relationship between NOX2 and Drp1. Knockdown Drp1 or gp91phox attenuated PA-induced NLRP3 induction and enhanced inhibitory effects of CRA. Oral administration of CRA in high-fat diet mice reproduced similar regulation in the aorta endothelium, further confirming its protection on endothelial homeostasis in vivo. Innovation: This study demonstrated that the defect in mitochondrial morphology is associated with the oxidative stress and NLRP3 inflammasome activation in the endothelium. Drp1 and NOX2 regulated each other and worked together to induce NLRP3 inflammasome activation, suggesting that modulation of Drp1 phosphorylation (Ser637) might be a potential therapeutic target for combating oxidative stress in vessel diseases. Conclusion: CRA prevented mitochondrial fission by regulation of Drp1 phosphorylation (Ser637) in an AMPK-dependent manner, and this action contributed to blocking NOX2 oxidase signaling and suppressing NLRP3 inflammasome activation in the endothelium. Antioxid. Redox Signal. 24, 893–908.
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