title: Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137.
abstract: Exogenous hydrogen sulfide (H2S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarbital-anesthetised rats were subjected to 30min of left coronary artery occlusion and 2h reperfusion. Infarct size was assessed by tetrazolium staining. In the first study, animals randomly received either no treatment or GYY4137 (26.6, 133 or 266μmolkg(-1)) by intravenous injection 10min before reperfusion. In a second series, involvement of PI3K and NO signalling were interrogated by concomitant administration of LY294002 or L-NAME respectively and the effects on the phosphorylation of Akt, eNOS, GSK-3β and ERK1/2 during early reperfusion were assessed by immunoblotting. GYY4137 266μmolkg(-1) significantly limited infarct size by 47% compared to control hearts (P<0.01). In GYY4137-treated hearts, phosphorylation of Akt, eNOS and GSK-3β was increased 2.8, 2.2 and 2.2 fold respectively at early reperfusion. Co-administration of L-NAME and GYY4137 attenuated the cardioprotection afforded by GYY4137, associated with attenuated phosphorylation of eNOS. LY294002 totally abrogated the infarct-limiting effect of GYY4137 and inhibited Akt, eNOS and GSK-3β phosphorylation. These data are the first to demonstrate that GYY4137 protects the heart against lethal reperfusion injury through activation of PI3K/Akt signalling, with partial dependency on NO signalling and inhibition of GSK-3β during early reperfusion. H2S-based therapeutic approaches may have value as adjuncts to reperfusion in the treatment of acute myocardial infarction.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, UK.
authors.forename: Qutuba G
authors.initials: QG
authors.lastname: Karwi
authors.affiliation: University of Exeter, Medical School, Exeter, UK EX1 2LU.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: School of Biosciences, University of Exeter, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.affiliation: University of Exeter, Medical School, Exeter, UK EX1 2LU; School of Biosciences, University of Exeter, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Torregrossa
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, UK. Electronic address: baxtergf@cardiff.ac.uk.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Baxter
mesh_terms: D000818:Animals; D019610:Cytoprotection; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D020011:Protective Agents; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D006862:Hydrogen Sulfide
keywords: GYY4137-Morphilino salt (PubChem CID: 469337261); Hydrogen sulfide; Ischemia-reperfusion; LY294002 (PubChem CID: 3973); Myocardial infarction; N-Nitro-l-arginine methyl ester hydrochloride (PubChem: 39836); Postconditioning; Reperfusion