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

doi:10.1016/j.redox.2021.101994

Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation

Redox Biol. 2021 Jul:43:101994. doi: 10.1016/j.redox.2021.101994. Epub 2021 Apr 30.

Authors

Wei Ou¹, Yu Liang², Yu Qin³, Wei Wu³, Maodi Xie², Yabing Zhang², Yarong Zhang⁴, Liwei Ji², Haiyang Yu⁴, Tao Li⁵

Affiliations

¹ 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.
² 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.
³ Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu, 610083, China.
⁴ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
⁵ 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. Electronic address: scutaoli1981@scu.edu.cn.

Abstract

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.

Keywords: Glucose metabolism; Heart; Hypoxia; Ischemia-reperfusion injury; Mitochondria; Redox homeostasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acclimatization
Animals
Homeostasis
Male
Mice
Myocardial Reperfusion Injury*
Oxidation-Reduction
Up-Regulation