Hydrogen sulfide protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis by preventing GSK-3beta-dependent opening of mPTP.
Hydrogen sulfide (H(2)S) is an endogenously generated gaseous transmitter, which has recently been suggested to regulate cardiovascular functions. The present study aims to clarify the mechanisms underlying the cardioprotective effects of H(2)S. Signaling elements were examined in cardiomyocytes cultured under hypoxia/reoxygenation conditions and in a rat model of ischemia-reperfusion. In cultured cardiomyocytes, sodium hydrosulfide (NaHS; 10, 30, and 50 mumol/l) showed concentration-dependent inhibitory effects on cardiomyocyte apoptosis induced by hypoxia/reoxygenation. These effects were associated with an increase in phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) (Ser9) and a decrease in Bax translocation, caspase-3 activation, and mitochondrial permeability transition pore (mPTP) opening. Transfection of a phosphorylation-resistant mutant of GSK-3beta at Ser9 attenuated the effects of NaHS in reducing cardiomyocyte apoptosis, Bax translocation, caspase-3 activation, and mPTP opening. In a rat model of ischemia-reperfusion, NaHS administration reduced myocardial infarct size and increased the phosphorylation of GSK-3beta (Ser9) at a dose of 30 mumol/kg. In conclusion, the H(2)S donor prevents cardiomyocyte apoptosis by inducing phosphorylation of GSK-3beta (Ser9) and subsequent inhibition of mPTP opening.
Dept. of Physiology and Pathophysiology, Fudan University Shanghai Medical College, 138 Yi Xue Yuan Rd., Shanghai, China.
Ling-Ling
LL
Yao
Xiao-Wei
XW
Huang
Yong-Gang
YG
Wang
Yin-Xiang
YX
Cao
Cai-Cai
CC
Zhang
Yi-Chun
YC
Zhu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053148:Caspase 3 / Q000096:biosynthesis; D061945:Caspase Inhibitors; D015687:Cell Hypoxia / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D020011:Protective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D061945:Caspase Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020011:Protective Agents; D051028:bcl-2-Associated X Protein; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D002118:Calcium; D006862:Hydrogen Sulfide