Sevoflurane postconditioning reduces myocardial ischemia reperfusion injury-induced necroptosis by up-regulation of OGT-mediated O-GlcNAcylated RIPK3
Jing Zhang, Peng Yu, Fuzhou Hua, Yanhui Hu, Fan Xiao, Qin Liu, Dan Huang, Fumou Deng, Gen Wei, Wei Deng, Jianyong Ma, Wengen Zhu, Jiru Zhang, Shuchun Yu
Abstract
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.