title: Hydrogen sulfide protects cardiomyocytes from myocardial ischemia-reperfusion injury by enhancing phosphorylation of apoptosis repressor with caspase recruitment domain.
abstract: Hydrogen sulfide (H(2)S) displays an anti-apoptotic activity against myocardial ischemia reperfusion (MIR).  Apoptosis repressor with caspase recruitment domain (ARC) is constitutively expressed in the heart and inhibits cell apoptosis when it is phosphorylated.  Here, we investigated whether H(2)S could inhibit apoptosis by affecting ARC phosphorylation using cultured rat cardiomyocytes and a rat model of MIR.  Primary cardiomyocytes were prepared from hearts of newborn rats and were pre-incubated with NaHS, a donor of H(2)S, for 60 min.  Cardiomyocytes were subjected to hypoxia for 4 h, followed by reoxygenation for 2 h.  The hypoxia and subsequent reoxygenation (H/R) significantly induced cell apoptosis, increased expression levels of Fas and FasL proteins, enhanced release of cytochrome c from mitochondria, and elevated caspase-3 activity, while H/R reduced ARC phosphorylation and increased the activity of calcineurin that dephosphorylates ARC.  Pre-incubation with NaHS significantly attenuated the above effects through promoting ARC phosphorylation by reducing calcineurin activity and by increasing the activity of protein kinase casein kinase II (CK2) that phosphorylates ARC.  In fact, TBB, a specific inhibitor of CK2, abolished the effects of NaHS.  In rats undergoing MIR, NaHS significantly reduced the myocardial infarct size, cell apoptosis, calcineurin activity, and the expression levels of Fas, FasL and cleaved caspase-3 proteins, while NaHS increased ARC phosphorylation.  In contrast, DL-propargylglycine, an inhibitor of cystathionine γ-lyase, the main enzyme for H(2)S production in hearts, showed opposite effects to NaHS.  The results indicate that H(2)S inhibits apoptosis of cardiomyocytes induced by MIR through enhancing ARC phosphorylation.
authors.affiliation: Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, P.R. China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Yao
authors.forename: Gang
authors.initials: G
authors.lastname: Tan
authors.forename: Changjun
authors.initials: C
authors.lastname: He
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Yina
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D047390:Casein Kinase II / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar
chemical_list: D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D009124:Muscle Proteins; C491788:Nol3 protein, rat; D007770:L-Lactate Dehydrogenase; D047390:Casein Kinase II; C505410:Casp3 protein, rat; D053148:Caspase 3; D006862:Hydrogen Sulfide