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Research Paper|Volume 12, Issue 24|pp 25452—25468

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

Jing Zhang1, Peng Yu2, Fuzhou Hua1, Yanhui Hu1, Fan Xiao1, Qin Liu1, Dan Huang1, Fumou Deng1, Gen Wei1, Wei Deng1, Jianyong Ma3, Wengen Zhu4, Jiru Zhang5, Shuchun Yu1
  • 1Department of Anesthesiology, The Second Affiliate Hospital of Nanchang University, Nanchang 330006, China
  • 2Department of Endocrinology and Metabolism, The Second Affiliate Hospital of Nanchang University, Nanchang 330006, China
  • 3Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
  • 4Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
  • 5Department of Anesthesiology, Affiliated Hospital of Jiangnan University (The Fourth People's Hospital in Wuxi City), Wuxi 214000, China
* Equal contribution
Received: June 29, 2020Accepted: August 15, 2020Published: November 20, 2020
https://doi.org/10.18632/aging.104146

Copyright: © 2020 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.