title: H₂S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase.
abstract: BACKGROUND
  Cystathionine γ-lyase (CSE) produces H2S via enzymatic conversion of L-cysteine and plays a critical role in cardiovascular homeostasis. We investigated the effects of genetic modulation of CSE and exogenous H2S therapy in the setting of pressure overload-induced heart failure.
  
  
  RESULTS
  Transverse aortic constriction was performed in wild-type, CSE knockout, and cardiac-specific CSE transgenic mice. In addition, C57BL/6J or CSE knockout mice received a novel H2S donor (SG-1002). Mice were followed up for 12 weeks with echocardiography. We observed a >60% reduction in myocardial and circulating H2S levels after transverse aortic constriction. CSE knockout mice exhibited significantly greater cardiac dilatation and dysfunction than wild-type mice after transverse aortic constriction, and cardiac-specific CSE transgenic mice maintained cardiac structure and function after transverse aortic constriction. H2S therapy with SG-1002 resulted in cardioprotection during transverse aortic constriction via upregulation of the vascular endothelial growth factor-Akt-endothelial nitric oxide synthase-nitric oxide-cGMP pathway with preserved mitochondrial function, attenuated oxidative stress, and increased myocardial vascular density.
  
  
  CONCLUSIONS
  Our results demonstrate that H2S levels are decreased in mice in the setting of heart failure. Moreover, CSE plays a critical role in the preservation of cardiac function in heart failure, and oral H2S therapy prevents the transition from compensated to decompensated heart failure in part via upregulation of endothelial nitric oxide synthase and increased nitric oxide bioavailability.
authors: Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, 550 Peachtree St NE, Atlanta, GA 30308, USA.
authors: Kazuhisa
authors: K
authors: Kondo
authors: Shashi
authors: S
authors: Bhushan
authors: Adrienne L
authors: AL
authors: King
authors: Sumanth D
authors: SD
authors: Prabhu
authors: Tariq
authors: T
authors: Hamid
authors: Steven
authors: S
authors: Koenig
authors: Toyoaki
authors: T
authors: Murohara
authors: Benjamin L
authors: BL
authors: Predmore
authors: Gabriel
authors: G
authors: Gojon
authors: Gabriel
authors: G
authors: Gojon
authors: Rui
authors: R
authors: Wang
authors: Naveena
authors: N
authors: Karusula
authors: Chad K
authors: CK
authors: Nicholson
authors: John W
authors: JW
authors: Calvert
authors: David J
authors: DJ
authors: Lefer
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003542:Cystathionine gamma-Lyase / Q000172:deficiency / Q000235:genetics; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D006862:Hydrogen Sulfide / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
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