TY - JOUR
T1 - Hydrogen sulfide protects against myocardial ischemia and reperfusion injury by activating AMP-activated protein kinase to restore autophagic flux
AU - Xie, Hong
AU - Xu, Qingrong
AU - Jia, Jia
AU - Ao, Guizhen
AU - Sun, Ying
AU - Hu, Lifang
AU - Alkayed, Nabil J.
AU - Wang, Chen
AU - Cheng, Jian
N1 - Funding Information:
The project is supported by the grants from National Science Foundation of China ( 81471336 , 81371278 , 81171246 ), the Natural Science Foundation of Jiangsu Province of China (Grant No: BK20141187 ), the Priority Academic Program Development of Jiangsu Higher Education Institutions of China , Science and Technology Program from Suzhou City (Grant No: SYS201317 ).
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/3/13
Y1 - 2015/3/13
N2 - How hydrogen sulfide (H2S) protects against myocardial ischemia-reperfusion (I/R) injury is poorly understood. By using a slow-releasing H2S donor, we investigated if H2S protected against myocardial I/R injury by activating AMPK and restoring I/R-impaired autophagic flux. Male rats received anterior descending coronary artery occlusion followed by reperfusion. The H2S donor ADT and/or the AMPK inhibitor, compound C (CC), were administered after occlusion. Infarction was analyzed histologically. AMPK activation was assessed in the ischemic heart by analyzing phosphorylation of AMPK and S6 ribosomal protein. Autophagy was assessed by analyzing the following markers: microtubule-associated protein 1 light chain 3 (LC3) I and II, lysosome associated membrane protein-2 (LAMP-2), P62 and beclin-1. We further investigated if blocking autophagic flux with chloroquine abolished ADT cardioprotection in vivo. Myocardial I/R reduced serum H2S levels, which was elevated by ADT. ADT enhanced AMPK activation and reduced infarction following I/R, and both effects were abolished by AMPK inhibition. Myocardial I/R induced autophagosome accumulation, as evidenced by the increased ratios of LC3-II/LC3-I, upregulation of beclin-1 and P62 and reduction in LAMP-2. ADT blunted these autophagic changes induced by I/R, indicating that ADT restored I/R-impaired autophagic flux. The AMPK inhibitor CC blocked ADT effects on restoring I/R-impaired autophagy flux. Moreover, chloroquine pretreatment abolished cardioprotection of ADT and increased autophagosome accumulation in the ADT-treated heart following I/R. In conclusion, AMPK activation and subsequent restoration of I/R-impaired autophagic flux are unrecognized mechanisms underlying cardioprotective effects conferred by H2S donors.
AB - How hydrogen sulfide (H2S) protects against myocardial ischemia-reperfusion (I/R) injury is poorly understood. By using a slow-releasing H2S donor, we investigated if H2S protected against myocardial I/R injury by activating AMPK and restoring I/R-impaired autophagic flux. Male rats received anterior descending coronary artery occlusion followed by reperfusion. The H2S donor ADT and/or the AMPK inhibitor, compound C (CC), were administered after occlusion. Infarction was analyzed histologically. AMPK activation was assessed in the ischemic heart by analyzing phosphorylation of AMPK and S6 ribosomal protein. Autophagy was assessed by analyzing the following markers: microtubule-associated protein 1 light chain 3 (LC3) I and II, lysosome associated membrane protein-2 (LAMP-2), P62 and beclin-1. We further investigated if blocking autophagic flux with chloroquine abolished ADT cardioprotection in vivo. Myocardial I/R reduced serum H2S levels, which was elevated by ADT. ADT enhanced AMPK activation and reduced infarction following I/R, and both effects were abolished by AMPK inhibition. Myocardial I/R induced autophagosome accumulation, as evidenced by the increased ratios of LC3-II/LC3-I, upregulation of beclin-1 and P62 and reduction in LAMP-2. ADT blunted these autophagic changes induced by I/R, indicating that ADT restored I/R-impaired autophagic flux. The AMPK inhibitor CC blocked ADT effects on restoring I/R-impaired autophagy flux. Moreover, chloroquine pretreatment abolished cardioprotection of ADT and increased autophagosome accumulation in the ADT-treated heart following I/R. In conclusion, AMPK activation and subsequent restoration of I/R-impaired autophagic flux are unrecognized mechanisms underlying cardioprotective effects conferred by H2S donors.
KW - AMP-activated protein kinase
KW - Autophagy
KW - Hydrogen sulfide
KW - Myocardial ischemia/reperfusion
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U2 - 10.1016/j.bbrc.2015.02.017
DO - 10.1016/j.bbrc.2015.02.017
M3 - Article
C2 - 25684185
AN - SCOPUS:84924057912
SN - 0006-291X
VL - 458
SP - 632
EP - 638
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -