title: GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia.
abstract: OBJECTIVE
  Myocardial infarction followed by adverse left ventricular (LV) remodeling is the most frequent proximate cause of heart failure. Hydrogen sulfide (H2S) is an important endogenous modulator of diverse physiological and pathophysiological processes. Its role in post-ischemic ventricular remodeling and the associated neurohormonal responses has not been defined. Here, we aimed at evaluating whether the slow-releasing water-soluble H2S donor GYY4137 (GYY) exerts cardioprotective effects and modulates the neurohormonal response to cardiac ischemic injury.
  
  
  RESULTS
  Treatment for 2 or 7 days with GYY (100 mg/Kg/48 h, IP) after acute myocardial infarction (MI) in rats preserved LV dimensions and function in vivo, compared to untreated infarcted (MI), placebo- and dl-propargylglycine- (PAG, an inhibitor of endogenous H2S synthesis) treated animals (n=9/group/time-point). LV dimensions and function in GYY-treated animals were comparable to healthy sham-operated rats. GYY-treated hearts had significantly less LV fibrosis than MI, placebo and PAG hearts. A higher density of blood vessels was found in the LV scar area of GYY-treated animals compared to all other infarcted groups. Despite preserved LV structure and function, treatment with GYY increased the levels of the natriuretic peptides ANP and BNP in association with enhanced cyclic GMP levels, paralleled by higher cGMP-dependent protein kinase type I (cGKI) protein levels.
  
  
  CONCLUSIONS
  Our data suggest that the slow-releasing H2S donor, GYY4137, preserves cardiac function, attenuates adverse remodeling and may exert post-ischemic cardioprotective (pro-angiogenic, anti-apoptotic, anti-hypertrophic and anti-fibrotic) effects in part through enhanced early post-ischemic endogenous natriuretic peptide activation.
authors.affiliation: Cardiovascular Research Institute, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Shera
authors.initials: S
authors.lastname: Lilyanna
authors.affiliation: Neurobiology Group, Life Sciences Institute and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Meng Teng
authors.initials: MT
authors.lastname: Peh
authors.affiliation: Cardiovascular Research Institute, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Oi Wah
authors.initials: OW
authors.lastname: Liew
authors.affiliation: Cardiovascular Research Institute, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Peipei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Neurobiology Group, Life Sciences Institute and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Moore
authors.affiliation: Cardiovascular Research Institute, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cardiac Department, National University Health System, Singapore; Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
authors.forename: Arthur Mark
authors.initials: AM
authors.lastname: Richards
authors.affiliation: Cardiovascular Research Institute, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: ecm37@med.miami.edu.
authors.forename: Eliana C
authors.initials: EC
authors.lastname: Martinez
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D009025:Morpholines / Q000008:administration & dosage; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage; D051381:Rats; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D006862:Hydrogen Sulfide
keywords: Angiogenesis; Hydrogen sulfide; Myocardial infarction; Natriuretic peptides; Remodeling