H2S restores the cardioprotective effects of ischemic post-conditioning by upregulating HB-EGF/EGFR signaling.

Yuanzhou Zhang,Yuehong Wang,Xin Wen,Weiming Sun,Yuxin Xi,Can Wei,Hongzhu Li,Jun Gao,Changqing Xu

doi:10.18632/aging.101866

Abstract

Hydrogen sulfide (H2S) reduces ischemia/reperfusion (I/R) injury and apoptosis and restores the cardioprotective effects of ischemic post-conditioning (PC) in aged cardiomyocytes by inhibiting oxidative stress and endoplasmic reticulum stress and increasing autophagy. However, the mechanism is unclear. In the present study, we observed a loss of PC-mediated cardioprotection of aged cardiomyocytes. NaHS (a H2S donor) exerted significant protective effects against H/R-induced cell damage, apoptosis, production of cleaved caspase-3 and caspase-9, and release of cytochrome c. NaHS also reversed the H/R-induced reduction in cell viability and increased HB-EGF expression, cellular HB-EGF content, and EGFR phosphorylation. Additionally, NaHS increased expression of Bcl-2, c-myc, c-fos and c-jun, and the phosphorylation of ERK1/2, PI3K, Akt and GSK-3β. PC alone did not provide protection to H/R-treated aged cardiomyocytes, but it was significantly restored by supplementation of NaHS. The beneficial effects of NaHS during PC were inhibited by EGFR knockdown, AG1478 (EGFR inhibitor), PD98059 (ERK1/2 inhibitor) or LY294002 (PI3K inhibitor). These results suggest that exogenous H2S restores PC-mediated cardioprotection by up-regulating HB-EGF/EGFR signaling, which activates the ERK1/2-c-myc (and fos and c-jun) and PI3K-Akt- GSK-3β pathways in the aged cardiomyocytes.

Highlights

Myocardial ischemia is a leading cause of morbidity and mortality worldwide [1]
H/R markedly reduced Heparin-binding epidermal growth factor (HB-EGF) expression and content in aged H9C2 cells, and that effect was reversed by treatment with NaHS
The beneficial effects of PC + NaHS on HB-EGF and EGF receptor (EGFR) levels were inhibited by AG1478, suggesting they were mediated via HB-EGF/EGFR signaling (Figure 1)

Summary

Introduction

The first choice for treatment of acute myocardial ischemia is reperfusion therapy, which reduces infarct size by restoring oxygen to the myocardium [2]. It can cause tissue damage due to the oxidative stress in can induce. This is known as ischemia/reperfusion (I/R) injury [3]. To reduce I/R injury, ischemic post-conditioning (PC) is used to reduce oxidative stress and mitochondrial permeability transition pore (mPTP) opening and to increase autophagy [4]. The beneficial effects of PC in ischemic myocardial cells may be weakened or even lost [9]

Methods

Results

Conclusion