Inhibition of Mitochondrial Oxidative Damage Improves Reendothelialization Capacity of Endothelial Progenitor Cells via SIRT3 (Sirtuin 3)-Enhancec SOD2 (Superoxide Dismutase 2) Deacetylation in Hypertension
Inhibition of Mitochondrial Oxidative Damage Improves Reendothelialization Capacity of Endothelial Progenitor Cells via SIRT3 (Sirtuin 3)-Enhancec SOD2 (Superoxide Dismutase 2) Deacetylation in Hypertension
复制标题
通过 SIRT3 (Sirtuin 3)-Enhancec SOD2（超氧化物歧化酶 2）去乙酰化抑制高血压，抑制线粒体氧化损伤可提高内皮祖细胞的再内皮化能力
DOI：
10.1161/atvbaha.119.312613
复制
发表时间：
2019-08-01
影响因子：
8.7
通讯作者：
Tao, Jun
中科院分区：
文献类型：
--
作者：
He, Jiang;Liu, Xing;Tao, Jun
目的：高血压病患者内皮祖细胞功能障碍导致内皮修复能力受损，但其机制尚不完全清楚。线粒体氧化应激参与高血压血管内皮细胞损伤。在本研究中，我们旨在探讨线粒体氧化应激在内皮细胞修复能力缺陷中的作用，并确定SIRT3(Sirtuin 3)介导的SOD2(超氧化物歧化酶2)脱乙酰化增强是高血压患者一种新的内皮保护机制。APPROACH和结果：高血压-EPC表现出线粒体活性氧增加和线粒体损伤，包括线粒体膜电位丧失、线粒体超微结构异常和线粒体DNA氧化损伤，这与体外功能和体内再内皮化能力受损的情况相一致。血管紧张素II共孵育体外模拟高血压对内皮祖细胞线粒体功能的影响。用Mito Tempo清除线粒体活性氧物种可减轻线粒体氧化损伤并挽救再内皮化能力。高血压内皮祖细胞SOD2的酶活性和去乙酰化水平显著降低，并伴有SIRT3表达的降低。内皮祖细胞中SIRT3基因的敲除导致线粒体氧化损伤、SOD2的高乙酰化和再内皮化能力的抑制。SIRT3与SOD2发生物理相互作用，通过K68去乙酰化增强SOD2的活性，消除线粒体过量的活性氧，恢复线粒体的功能。SIRT3/SOD2信号通路上调可改善EPC的再内皮化能力。结论：本研究首次证实SIRT3/SOD2信号通路缺陷引起的线粒体氧化损伤是高血压EPC再内皮化能力下降的原因之一。维持内皮祖细胞线粒体氧化还原动态平衡可能是治疗内皮损伤的新靶点。
OBJECTIVE: Dysfunction of endothelial progenitor cells (EPCs) leads to impaired endothelial repair capacity in patients with hypertension, but the mechanisms remain incompletely understood. Mitochondrial oxidative stress is involved in endothelial injury in hypertension. In this study, we aim to investigate the role of mitochondria) oxidative stress in the deficient endothelial reparative capacity of EPCs and identify enhanced SIRT3 (sirtuin 3)-mediated SOD2 (superoxide dismutase 2) deacetylation as a novel endothelial protective mechanism in hypertension.APPROACH AND RESULTS: Hypertension-EPCs displayed increased mitochondrial reactive oxygen species and mitochondrial damage, including loss of mitochondrial membrane potential, abnormal mitochondrial ultrastructure, and mtDNA oxidative injury, which was coincided with impaired in vitro function and in vivo reendothelialization capacity. The harmful effects of hypertension on mitochondrial function of EPCs were in vitro mimicked by angiotensin II coincubation. Scavenging of mitochondrial reactive oxygen species with mito TEMPO attenuated mitochondrial oxidative damage and rescued reendothelialization capacity. Enzymatic activity and deacetylation level of SOD2 were significantly reduced in hypertension-EPCs, which was accompanied with decreased SIRT3 expression. Knockdown of SIRT3 in EPCs resulted in mitochondrial oxidative damage, hyperacetylation of SOD2, and suppression of reendothelialization capacity. SIRT3 physically interacted with SOD2 and eliminated excess mitochondrial reactive oxygen species, restored mitochondrial function through enhancing SOD2 activity by deacetylation of K68. Upregulation of SIRT3/SOD2 signaling improved reendothelialization capability of EPCs.CONCLUSIONS: The present study demonstrated for the first time that mitochondrial oxidative damage because of deficient SIRT3/SOD2 signaling contributes to the decline in reendothelialization capacity of EPCs in hypertension. Maintenance of mitochondrial redox homeostasis in EPCs may be a novel therapeutic target for endothelial injury.