Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation
Wei Ou,
Yu Liang,
Yu Qin,
Wei Wu,
Maodi Xie,
Yabing Zhang,
Yarong Zhang,
Liwei Ji,
Haiyang Yu,
Tao Li
Affiliations
Wei Ou
Laboratory of Mitochondria and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Anesthesia and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China; Department of Anesthesiology, Nanchong Central Hospital, Nanchong, 637000, China
Yu Liang
Laboratory of Mitochondria and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Anesthesia and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
Yu Qin
Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu, 610083, China
Wei Wu
Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu, 610083, China
Maodi Xie
Laboratory of Mitochondria and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Anesthesia and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
Yabing Zhang
Laboratory of Mitochondria and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Anesthesia and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
Yarong Zhang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
Liwei Ji
Laboratory of Mitochondria and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Anesthesia and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
Haiyang Yu
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
Tao Li
Laboratory of Mitochondria and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Anesthesia and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China; Corresponding author. West China Hospital, Sichuan University No 37 Wainan Guoxue Road, Chengdu, Sichuan 610041, China.
Ischemia-reperfusion (I/R) injury is detrimental to cardiovascular system. Alteration in glucose metabolism has been recognized as an important adaptive response under hypoxic conditions. However, the biological benefits underlying this metabolic phenotype remain to be elucidated. This study was designed to investigate the impact of hypoxic acclimation (HA) on cardiac I/R injury and the antioxidative mechanism(s). Male adult mice were acclimated in a hypoxic chamber (10% oxygen [O2]) for 8 h/day for 14 days, and then subjected to cardiac I/R injury by ligation of left anterior descending coronary artery for 30 min and reperfusion for 24 h or 7 days. Our results showed that HA attenuated oxidative stress and reduced infarct size in the I/R hearts. This cardioprotective effect is coupled with an elevation of protein O-linked N-acetylglucosamine (O-GlcNAc) modification partially due to inflammatory stimulation. Hyperglycosylation activated glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway, resulting in an upregulation of NADPH/NADP+ and GSH/GSSG couples and enhancement of redox homeostasis in the heart. Pharmacological suppression of O-GlcNAcylation totally abolished the influence of HA on the G6PDH activity, redox balance and post-I/R damage in the hearts and cultured cardiomyocytes, whereby augmentation of O-GlcNAcylation further enhanced the benefits, suggesting a central role of O-GlcNAcylation in HA-initiated antioxidative and cardioprotective effects. These findings, therefore, identified HA as a promising anti-I/R strategy for the heart and proposed O-GlcNAc modification of G6PDH as a therapeutic target in ischemic heart disease.
