Genetic and Pharmacologic Hydrogen Sulfide Therapy Attenuates Ischemia-Induced Heart Failure in Mice

• Type of Material: Article
• Authors: John W Calvert, Emory University; Marah Elston, Emory University; Chad K. Nicholson, Emory University; Susheel Gundewar, Albert Einstein College; Saurabh Jha, Albert Einstein College; John W. Elrod, Cincinnati Children’s Hospital Medical Center; Arun Ramachandran, Albert Einstein College; David J. Lefer, Emory University
• Language: English
• Date: 2010-07-06
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 American Heart Association, Inc.
• Final Published Version (URL): http://circ.ahajournals.org/content/122/1/11
• Title of Journal or Parent Work: Circulation
• ISSN: 0009-7322
• Volume: 122
• Issue: 1
• Start Page: 11
• End Page: 19
• Grant/Funding Information: This work was supported by grants from the American Diabetes Association (7-09-BS-26 to Dr Calvert) and the National Heart, Lung, and Blood Institute (National Institutes of Health; 2R01HL-060849-09, 5R01HL-092141-01, and 1R01HL093579-01 to Dr Lefer, 1R01HL098481-01 to Dr Calvert, and F32HL092737 to Dr Elrod). This work was also supported by funding from the Carlyle Fraser Heart Center of Emory University Hospital Midtown.; National Heart, Lung, and Blood Institute : NHLBI
• Keywords: ischemia; hydrogen sulfide; myocardial infarction; heart failure; cystathionine γ-Lyase
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Background Hydrogen sulfide (H2S) is an endogenous signaling molecule with potent cytoprotective effects. The present study evaluated the therapeutic potential of H2S in murine models of heart failure. Methods and Results Heart failure was induced by subjecting mice either to permanent ligation of the left coronary artery for 4 weeks or to 60 minutes of left coronary artery occlusion followed by reperfusion for 4 weeks. Transgenic mice with cardiac-restricted overexpression of the H2S-generating enzyme cystathione γ-lyase (αMHC-CGL-Tg+) displayed a clear protection against left ventricular structural and functional impairment as assessed by echocardiography in response to ischemia-induced heart failure, as well as improved survival in response to permanent myocardial ischemia. Exogenous H2S therapy (Na2S; 100 μg/kg) administered at the time of reperfusion (intracardiac) and then daily (intravenous) for the first 7 days after myocardial ischemia also protected against the structural and functional deterioration of the left ventricle by attenuating oxidative stress and mitochondrial dysfunction. Additional experiments aimed at elucidating some of the protective mechanisms of H2S therapy found that 7 days of H2S therapy increased the phosphorylation of Akt and increased the nuclear localization of 2 transcription factors, nuclear respiratory factor 1 and nuclear factor-E2-related factor (Nrf2), that are involved in increasing the levels of endogenous antioxidants, attenuating apoptosis, and increasing mitochondrial biogenesis. Conclusions The results of the present study suggest that either the administration of exogenous H2S or the modulation of endogenous H2S production may be of therapeutic benefit in the treatment of ischemia-induced heart failure.