title: Nitroxyl (HNO) stimulates soluble guanylyl cyclase to suppress cardiomyocyte hypertrophy and superoxide generation.
abstract: BACKGROUND
  New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NO• attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) however has not been investigated.
  
  
  METHODS
  Neonatal rat cardiomyocytes were incubated with angiotensin II (Ang II) in the presence and absence of the HNO donor Angeli's salt (sodium trioxodinitrate) or B-type natriuretic peptide, BNP (all 1 µmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined.
  
  
  RESULTS
  We now demonstrate that Angeli's salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and β-myosin heavy chain expression. Angeli's salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation), as well as p38 mitogen-activated protein kinase (p38MAPK). The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeli's salt were mimicked by BNP. We also demonstrate that the effects of Angeli's salt are specifically mediated by HNO (with no role for NO• or nitrite), with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC) and cGMP signaling (on both cGMP-dependent protein kinase, cGK-I and phosphorylation of vasodilator-stimulated phosphoprotein, VASP).
  
  
  CONCLUSIONS
  Our results demonstrate that HNO prevents cardiomyocyte hypertrophy, and that cGMP-dependent NADPH oxidase suppression contributes to these antihypertrophic actions. HNO donors may thus represent innovative pharmacotherapy for cardiac hypertrophy.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Eliane Q
authors.initials: EQ
authors.lastname: Lin
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Irvine
authors.forename: Anh H
authors.initials: AH
authors.lastname: Cao
authors.forename: Amy E
authors.initials: AE
authors.lastname: Alexander
authors.forename: Jane E
authors.initials: JE
authors.lastname: Love
authors.forename: Ruchi
authors.initials: R
authors.lastname: Patel
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D009573:Nitrites / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013481:Superoxides / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D019332:Endothelin-1; D008840:Microfilament Proteins; D009573:Nitrites; D009589:Nitrogen Oxides; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D000098662:Vasodilator-Stimulated Phosphoprotein; D013481:Superoxides; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; C021229:oxyhyponitrite; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C039900:nitroxyl; D006152:Cyclic GMP