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Research Paper|Volume 11, Issue 6|pp 1745—1758

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

Yuanzhou Zhang1,3, Jun Gao2, Weiming Sun1,3, Xin Wen1,3, Yuxin Xi1,3, Yuehong Wang1,3, Can Wei1,3, Changqing Xu1,3, Hongzhu Li1,3
  • 1Department of Pathophysiology, Harbin Medical University, Harbin, China
  • 2Department of Osteology, the First Hospital of Harbin, Harbin, China
  • 3The Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Harbin, China

* * Equal contribution

Received: January 25, 2018Accepted: March 7, 2019Published: March 26, 2019
https://doi.org/10.18632/aging.101866

Copyright: © 2019 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

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.