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

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 [O 2 ]) 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.

Obesity by High-Fat Diet Increases Pain Sensitivity by Reprogramming Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia

“…Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed after 8 weeks on HFD and CD, as described previously ( 11 ). Prior to ITT and GTT, mice were fasted for 4 or 6 h, respectively.…”

Enhancement of O-GlcNAcylation on Mitochondrial Proteins with 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, Contributes to the Mitochondrial Network, Cellular Bioenergetics and Stress Response in Neuronal Cells under Ischemic-like Conditions

“…Emerging evidence suggests that O -GlcNAc signaling contributes to mitochondria metabolism and homeostasis, as well as cellular stress response [ 31 ]. During myocardial ischemia-reperfusion injury, augmentation of O -GlcNAcylation alleviates mitochondrial dysfunction, including improving mitochondrial redox homeostasis, inhibiting MPTP formation and MMP loss, and maintaining mitochondrial bioenergy, thus contributing to cardioprotection [ 32 , 33 , 34 ]. Most recently, Park et al report that mitochondrial protein O -GlcNAcylation is a critical process supporting functional extracellular mitochondrial secretion of astrocytes, which can promote neuronal survival and improve stroke outcome [ 35 ].…”

Ketone Body β-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy

“…The cardiac mitochondria were isolated using differential centrifugation described previously [ 30 ]. Briefly, freshly isolated hearts were rinsed with cold sucrose-containing mitochondrial isolation buffer, chopped into pieces, and then homogenized in mitochondrial isolation buffer using the Dounce homogenizer with Teflon pestle.…”