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.