TY - JOUR T1 - Cardioprotection by H2S engages a cGMP-dependent protein kinase G/phospholamban pathway JF - Cardiovasc ResCardiovasc ResCardiovasc Res Y1 - 2015 A1 - Bibli, S. I. A1 - Andreadou, I. A1 - Chatzianastasiou, A. A1 - Tzimas, C. A1 - Sanoudou, D. A1 - Kranias, E. A1 - Brouckaert, P. A1 - Coletta, C A1 - Szabo, C. A1 - Kremastinos, D.T. A1 - Iliodromitis, E.K. A1 - Papapetropoulos, A. KW - Animals KW - Calcium-Binding Proteins/deficiency/genetics/*metabolism KW - Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors/*metabolism KW - Cyclic GMP/metabolism KW - Disease Models, Animal KW - Enzyme Activation KW - Female KW - Hydrogen Sulfide/metabolism/*pharmacology KW - Male KW - Mice, Inbred C57BL KW - Mice, Knockout KW - Myocardial Infarction/enzymology/pathology/*prevention & control KW - Myocardial Reperfusion Injury/enzymology/pathology/*prevention & control KW - Myocytes, Cardiac/*drug effects/enzymology/pathology KW - Nitric Oxide Synthase Type III/antagonists & inhibitors/genetics/metabolism KW - Nitric Oxide/metabolism KW - Phosphorylation KW - Protein Kinase Inhibitors/pharmacology KW - Rabbits KW - Signal Transduction/*drug effects KW - Species Specificity KW - Sulfides/metabolism/*pharmacology AB - AIMS: H2S is known to confer cardioprotection; however, the pathways mediating its effects in vivo remain incompletely understood. The purpose of the present study is to evaluate the contribution of cGMP-regulated pathways in the infarct-limiting effect of H2S in vivo. METHODS AND RESULTS: Anaesthetized rabbits were subjected to myocardial ischaemia (I)/reperfusion (R), and infarct size was determined in control or H2S-exposed groups. The H2S donor sodium hydrosulfide (NaHS, an agent that generates H2S) increased cardiac cGMP and reduced the infarct size. The cGMP-dependent protein kinase (PKG)-I inhibitor DT2 abrogated the protective effect of NaHS, whereas the control peptide TAT or l-nitroarginine methyl ester (l-NAME) did not alter the effect of NaHS. Moreover, the KATP channel inhibitor, glibenclamide, partially reversed the effects of NaHS, whereas inhibition of mitochondrial KATP did not modify the NaHS response. NaHS enhanced phosphorylation of phospholamban (PLN), in a PKG-dependent manner. To further investigate the role of PLN in H2S-mediated cardioprotection, wild-type and PLN KO mice underwent I/R. NaHS did not exert cardioprotection in PLN KO mice. Unlike what was observed in rabbits, genetic or pharmacological inhibition of eNOS abolished the infarct-limiting effect of NaHS in mice. CONCLUSIONS: Our findings demonstrate (i) that administration of NaHS induces cardioprotection via a cGMP/PKG/PLN pathway and (ii) contribution of nitric oxide to the H2S response is species-specific. VL - 106 SN - 1755-3245 (Electronic)0008-6363 (Linking) N1 - Bibli, Sofia-IrisAndreadou, IoannaChatzianastasiou, AthanasiaTzimas, ChristosSanoudou, DespinaKranias, EvangeliaBrouckaert, PeterColetta, CiroSzabo, CsabaKremastinos, Dimitrios ThIliodromitis, Efstathios KPapapetropoulos, AndreasengR01 GM107846/GM/NIGMS NIH HHS/R01 HL026057/HL/NHLBI NIH HHS/R01 HL064018/HL/NHLBI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tEngland2015/04/15 06:00Cardiovasc Res. 2015 Jun 1;106(3):432-42. doi: 10.1093/cvr/cvv129. Epub 2015 Apr 13. U2 - 4447809 JO - Cardiovascular researchCardiovascular research ER -