Sevoflurane Pre-conditioning Ameliorates Diabetic Myocardial Ischemia/Reperfusion Injury Via Differential Regulation of p38 and ERK

Dina Xie,Erhe Gao,Jimin Cao,Liyuan Jiao,Wayne Bond Lau,Xinliang Ma,Yajing Wang,Rui Guo,Bernard Lopez,Theodore Christopher,Jianli Zhao,Yanqing Zhang

doi:10.1038/s41598-019-56897-8

Abstract

Diabetes mellitus (DM) significantly increases myocardial ischemia/reperfusion (MI/R) injury. During DM, cardioprotection induced by conventional pre-conditioning (PreCon) is decreased due to impaired AMP-activated protein kinase (AMPK) signaling. The current study investigated whether PreCon with inhaled anesthetic sevoflurane (SF-PreCon) remains cardioprotective during DM, and identified the involved mechanisms. Normal diet (ND) and high-fat diet (HFD)-induced DM mice were randomized into control and SF-PreCon (3 cycles of 15-minute period exposures to 2% sevoflurane) groups before MI/R. SF-PreCon markedly reduced MI/R injury in DM mice, as evidenced by improved cardiac function (increased LVEF and ±Dp/dt), decreased infarct size, and decreased apoptosis. To determine the relevant role of AMPK, the effect of SF-PreCon was determined in cardiac-specific AMPKα2 dominant negative expressing mice (AMPK-DN). SF-PreCon decreased MI/R injury in AMPK-DN mice. To explore the molecular mechanisms responsible for SF-PreCon mediated cardioprotection in DM mice, cell survival molecules were screened. Interestingly, in ND mice, SF-PreCon significantly reduced MI/R-induced activation of p38, a pro-death MAPK, without altering ERK and JNK. In DM and AMPK-DN mice, the inhibitory effect of SF-PreCon upon p38 activation was significantly blunted. However, SF-PreCon significantly increased phosphorylation of ERK1/2, a pro-survival MAPK in DM and AMPK-DN mice. We demonstrate that SF-PreCon protects the heart via AMPK-dependent inhibition of pro-death MAPK in ND mice. However, SF-PreCon exerts cardioprotective action via AMPK-independent activation of a pro-survival MAPK member in DM mice. SF-PreCon may be beneficial compared to conventional PreCon in diabetes or clinical scenarios in which AMPK signaling is impaired.

Highlights

Www.nature.com/scientificreports report demonstrated sevoflurane is an AMPK activator[9]
SF-PreCon significantly improved cardiac function in Normal diet (ND) mice, as evidenced by increased left ventricular ejection fraction (LVEF, +8.9% compared to myocardial ischemia/reperfusion (MI/R), P < 0.05 Fig. 1A) and increased ±Dp/dt (23.7% and 23.4% compared to myocardial ischemia (MI)/R, P < 0.05, Fig. 1C)
Representative 3-dimensional wall velocity diagrams for 3 consecutive cardiac cycles are shown from animals at baseline (Sham, MI/R, and SF-PreCon treatment groups, Fig. 1B)

Summary

Introduction

Www.nature.com/scientificreports report demonstrated sevoflurane is an AMPK activator[9]. Whether any potential benefit of sevoflurane preconditioning against MI/R injury in a diabetic heart is associated with AMPK remains unknown. The present study determined whether sevoflurane preconditioning (SF-PreCon) in a high-fat diet induced diabetic model diminishes MI/R-induced cardiac injury. Employing AMPKα2 dominant negative expressing (AMPK-DN) mice, we determined the influence of AMPK signaling on the observed effects

Methods

Results

Discussion

Conclusion