Hyper-O-GlcNAcylation impairs insulin response against reperfusion-induced myocardial injury and arrhythmias in obesity

Autor: Caiyao Li, Xinghua Qin, Binghua Liu, Tiannan Jiang, Qiangsun Zheng, Feng Gao, Lingyan Jin
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
Cardiotonic Agents
Glycosylation
medicine.medical_treatment
Norleucine
Diazooxonorleucine
Biophysics
Myocardial Reperfusion Injury
medicine.disease_cause
Biochemistry
Acetylglucosamine
Cell Line
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Glucosamine
Internal medicine
medicine
Animals
Humans
Insulin
Myocardial infarction
Obesity
Molecular Biology
Cardioprotection
business.industry
Myocardium
Arrhythmias
Cardiac
Cell Biology
medicine.disease
Cell Hypoxia
Mice
Mutant Strains
Rats
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Endocrinology
chemistry
030220 oncology & carcinogenesis
Biomarker (medicine)
business
Reperfusion injury
Protein Processing
Post-Translational
Oxidative stress
Zdroj: Biochemical and biophysical research communications. 558
ISSN: 1090-2104
Popis: Myocardial ischemia/reperfusion (I/R) injury is a major determinant of morbidity and mortality in patients undergoing treatment for cardiac disease. A variety of treatments are reported to have benefits against reperfusion injury, yet their cardioprotective effects seem to be diminished in obesity, and the underlying mechanism remains elusive. In this study, we found that db/db mice exhibit cardiac hyper-O-GlcNAcylation. In parallel, palmitate treatment (200 mM; 12 h) in H9c2 cells showed an increase in global protein O-GlcNAcylation, along with an impaired insulin response against reperfusion injury. To investigate whether O-GlcNAcylation underlies this phenomenon, glucosamine was used to increase global protein O-GlcNAc levels. Interestingly, histological staining, electrophysiological studies, serum cardiac markers and oxidative stress biomarker assays showed that preischemic treatment with glucosamine attenuated insulin cardioprotection against myocardial infarction, arrhythmia and oxidative stress. Mechanistically, glucosamine treatment decreased insulin-stimulated Akt phosphorylation, a key modulator of cell survival. Furthermore, inhibition of O-GlcNAcylation via 6-diazo-5-oxo- l -norleucine (DON) apparently increased insulin-induced Akt phosphorylation and restored its cardioprotective response against reperfusion injury in palmitate-induced insulin-resistant H9c2 cells. Our findings demonstrated that obesity-induced hyper-O-GlcNAcylation might contribute to the attenuation of insulin cardioprotection against I/R injury.
Databáze: OpenAIRE
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