Targeting mitochondria-inflammation circle by renal denervation reduces atheroprone endothelial phenotypes and atherosclerosis

作者：Zhuqing Li, Qi Li, Li Wang, Chao Li, Mengping Xu, Yajun Duan, Likun Ma, Tingting Li, Qiao Chen, Yilin Wang, Yanxin Wang, Jiaxin Feng, Xuemei Yin, Xiaolin Wang, Jihong Han, Chengzhi Lu · 发表于：Redox Biology · 年份：2021 · DOI：10.1016/j.redox.2021.102156 · 被引用次数：48 · 研究领域：Sodium Intake and Health、Nitric Oxide and Endothelin Effects、Dialysis and Renal Disease Management

OBJECTIVE: The disruption of mitochondrial redox homeostasis in endothelial cells (ECs) can cause chronic inflammation, a substantial contributor to the development of atherosclerosis. Chronic sympathetic hyperactivity can enhance oxidative stress to induce endothelial dysfunction. We determined if renal denervation (RDN), the strategy reducing sympathetic tone, can protect ECs by ameliorating mitochondrial reactive oxygen species (ROS)-induced inflammation to reduce atherosclerosis. METHODS AND RESULTS: ) mice were conducted RDN or sham operation before 20-week high-fat diet feeding. Atherosclerosis, EC phenotype and mitochondrial morphology were determined. In vitro, human arterial ECs were treated with norepinephrine to determine the mechanisms for RDN-inhibited endothelial inflammation. RDN reduced atherosclerosis, EC mitochondrial oxidative stress and inflammation. Mechanistically, the chronic sympathetic hyperactivity increased circulating norepinephrine and mitochondrial monoamine oxidase A (MAO-A) activity. MAO-A activation-impaired mitochondrial homeostasis resulted in ROS accumulation and NF-κB activation, thereby enhancing expression of atherogenic and proinflammatory molecules in ECs. It also suppressed mitochondrial function regulator PGC-1α, with involvement of NF-κB and oxidative stress. Inactivation of MAO-A by RDN disrupted the positive-feedback regulation between mitochondrial dysfunction and inflammation, thereby inhibiting EC atheroprone phenotypic alterat...