From the Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (J.H., X.L., C.S., F.W., J.S., J.Z., X.Y., C.Z., Z.Z., X.Z., J.T.).
Department of Cardiology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China (X.L.).
Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1682-1698. doi: 10.1161/ATVBAHA.119.312613. Epub 2019 Jun 13.
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 mitochondrial 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 mitoTEMPO 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.
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.
内皮祖细胞（EPCs）功能障碍导致高血压患者内皮修复能力受损，但机制尚不完全清楚。线粒体氧化应激参与高血压内皮损伤。本研究旨在探讨线粒体氧化应激在 EPCs 内皮修复能力缺陷中的作用，并确定增强 SIRT3（沉默调节蛋白 3）介导的 SOD2（超氧化物歧化酶 2）去乙酰化作为高血压中一种新的内皮保护机制。
高血压-EPCs 显示线粒体活性氧和线粒体损伤增加，包括线粒体膜电位丧失、异常的线粒体超微结构和 mtDNA 氧化损伤，这与体外功能和体内再内皮化能力受损相吻合。血管紧张素 II 共孵育体外模拟了高血压对 EPCs 线粒体功能的有害影响。用 mitoTEMPO 清除线粒体活性氧减轻了线粒体氧化损伤并挽救了再内皮化能力。高血压-EPCs 中 SOD2 的酶活性和去乙酰化水平显著降低，同时 SIRT3 表达减少。EPCs 中 SIRT3 的敲低导致线粒体氧化损伤、SOD2 过度乙酰化和再内皮化能力抑制。SIRT3 与 SOD2 物理相互作用，消除多余的线粒体活性氧，通过 K68 去乙酰化增强 SOD2 活性来恢复线粒体功能。上调 SIRT3/SOD2 信号转导可改善 EPCs 的再内皮化能力。
本研究首次证明，由于 SIRT3/SOD2 信号转导不足导致的线粒体氧化损伤导致高血压中 EPCs 的再内皮化能力下降。维持 EPCs 中的线粒体氧化还原稳态可能是内皮损伤的一个新的治疗靶点。
