H₂S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase

Circulation. 2013 Mar 12;127(10):1116-27. doi: 10.1161/CIRCULATIONAHA.112.000855. Epub 2013 Feb 7.

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.

Methods and 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / therapeutic use*
  • Cystathionine gamma-Lyase / deficiency
  • Cystathionine gamma-Lyase / genetics
  • Heart Failure / drug therapy*
  • Heart Failure / enzymology*
  • Heart Failure / physiopathology
  • Hydrogen Sulfide / administration & dosage
  • Hydrogen Sulfide / therapeutic use*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nitric Oxide Synthase Type III / biosynthesis*
  • Nitric Oxide Synthase Type III / physiology
  • Up-Regulation / drug effects*
  • Up-Regulation / physiology

Substances

  • Cardiotonic Agents
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide