Sevoflurane postconditioning reduces myocardial ischemia reperfusion injury-induced necroptosis by up-regulation of OGT-mediated O-GlcNAcylated RIPK3

• Published in: Aging (Albany, NY.) NY.), 2020-11, Vol.12 (24), p.25452-25468
• Main Authors: Zhang, Jing, Yu, Peng, Hua, Fuzhou, Hu, Yanhui, Xiao, Fan, Liu, Qin, Huang, Dan, Deng, Fumou, Wei, Gen, Deng, Wei, Ma, Jianyong, Zhu, Wengen, Zhang, Jiru, Yu, Shuchun
• Format: Article
• Language: English
• Subjects: Acetylation; Anesthetics, Inhalation - pharmacology; Animals; Male; Myocardial Infarction - pathology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; N-Acetylglucosaminyltransferases - metabolism; Necroptosis - drug effects; Rats; Rats, Sprague-Dawley; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Research Paper; Sevoflurane - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Up-Regulation
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.104146

Inhalation anesthetics have been demonstrated to have protective effects against myocardial ischemia reperfusion injury (MIRI). O-linked GlcNAcylation (O-GlcNAc) modifications have been shown to protect against MIRI. This study aimed to investigate whether O-GlcNAcylation and necroptosis signaling were important for sevoflurane postconditioning (SPC) induced cardioprotective effects. Apart from rats in the SHAM and sevoflurane (SEVO) group, rats underwent 30 min ischemia followed by 2 h reperfusion. Cardiac hemodynamics and function were determined. In addition, myocardial infarction size, cardiac function parameters, myocardial lactic dehydrogenase (LDH) content, myocardium histopathological changes, necrotic myocardium, O-GlcNAcylation, and protein expression levels of necroptosis biomarkers were measured, together with co-immunoprecipitation experiments using proteins associated with the necroptosis pathway and O-GlcNAcylation. SPC reduced myocardial infarction size, ameliorated cardiac function, restored hemodynamic performance, improved histopathological changes, and reduced receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like (MLKL) mediated necroptosis. In addition, SPC up-regulated O-GlcNAc transferase (OGT) mediated O-GlcNAcylation, increased O-GlcNAcylated RIPK3, and inhibited the association of RIPK3 and MLKL. However, OSMI-1, an OGT inhibitor, abolished SPC mediated cardioprotective effects and inhibited OGT mediated up-regulation of O-GlcNAcylation and down-regulation of RIPK3 and MLKL proteins induced by SPC. Our study demonstrated that SPC restrained MIRI induced necroptosis via regulating OGT mediated O-GlcNAcylation of RIPK3 and lessening the formulation of RIPK3/MLKL complex.