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

Kazuhisa Kondo, Shashi Bhushan, Adrienne L. King, Sumanth D. Prabhu, Tariq Hamid, Steven Koenig, Toyoaki Murohara, Benjamin L. Predmore, Gabriel Gojon, Rui Wang, Naveena Karusula, Chad K. Nicholson, John W. Calvert, David J. Lefer

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

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 H 2S 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.

Original languageEnglish
Pages (from-to)1116-1127
Number of pages12
JournalCirculation
Volume127
Issue number10
DOIs
StatePublished - Mar 12 2013

Keywords

  • cyclic GMP
  • hypertrophy
  • left
  • nitric oxide
  • vascular endothelial growth factor
  • ventricular function

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