Document Type
Article
Publication Date
1-8-2020
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.
Recommended Citation
Xie, Dina; Zhao, Jianli; Guo, Rui; Jiao, Liyuan; Zhang, Yanqing; Lau, Wayne Bond; Lopez, Bernard; Christopher, Theodore; Gao, Erhe; Cao, Jimin; Ma, Xin-Liang; and Wang, Yajing, "Sevoflurane Pre-conditioning Ameliorates Diabetic Myocardial Ischemia/Reperfusion Injury Via Differential Regulation of p38 and ERK." (2020). Department of Emergency Medicine Faculty Papers. Paper 100.
https://jdc.jefferson.edu/emfp/100
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
31913350
Language
English
Comments
This article is the author’s final published version in Scientific Reports, Volume 10, Issue 1, January 2020, Article number 23.
The published version is available at https://doi.org/10.1038/s41598-019-56897-8. Copyright © Xie et al.
Publication made possible in part by support from the Thomas Jefferson University + Philadelphia University Open Access Fund