Inhibition of Mitochondrial Oxidative Damage Improves Reendothelialization Capacity of Endothelial Progenitor Cells via SIRT3 (Sirtuin 3)-Enhanced SOD2 (Superoxide Dismutase 2) Deacetylation in Hypertension

Abstract

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 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. 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.

Incretin drugs effect on epigenetic machinery: New potential therapeutic implications in preventing vascular diabetic complications

“…The role of the activation of NF-κB mediated signal transduction and of an enhanced mitochondrial oxidative stress at different stages of atherosclerosis, beginning from plaque formation to its destabilization and rupture, is well known. 29,30 Interestingly, our "in vitro" data showed that in endothelial cells, hyperglycemia evoked a significant demethylation in CpG islands located in promoter region of NF-κB and SOD2. In agreement with DNA methylation modification, HG exposure induced a TET2 upregulation and an increase of NF-κB and NFKB target gene expression.…”

“…Thus, to better clarify, the potential role of incretin‐based treatment in preventing and/or reverting the DNA methylation changes induced by HG, the effects of GLP‐1 or exenatide on DNMTs and TET2 expression and DNA methylation of NF‐κB and SOD2 has been evaluated in aortic endothelial cells exposed to high glucose for 7 days and co‐treated with GLP‐1 or exenatide. The role of the activation of NF‐κB mediated signal transduction and of an enhanced mitochondrial oxidative stress at different stages of atherosclerosis, beginning from plaque formation to its destabilization and rupture, is well known 29,30 …”

Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

“…4 A), and this increase was associated with significant downregulation of the antioxidant proteins Gpx1, HO-1, and SOD2, as well as the deacetylase SIRT3 ( Fig. 4 B) [ 29 ]. Additionally, we showed that not just the expression but also the activity of SOD2 was significantly inhibited in Mel-SHK-treated HeLa cells ( Fig.…”

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

“…In addition, SIRT3 can protect endothelial cells from mitochondrial ROS damage and increase NO release to benefit vasodilatation 159 . Moreover, SIRT3-mediated SOD2 deacetylation also contributes to maintaining the escape of endothelial progenitor cells (EPCs) from dysfunction and injury as well as decreased vascular inflammation 161 , 162 . Maternal obesity is another key problem in human beings.…”