H2S Protects Against Pressure Overload Induced Heart Failure via Upregulation of Endothelial Nitric Oxide Synthase (eNOS)

• Type of Material: Article
• Authors: Kazuhisa Kondo, Emory University; Shashi Bhushan, Emory University; Adrienne L. King, Emory University; Sumanth D. Prabhu, University of Alabama-Birmingham; Tariq Hamid, University of Alabama-Birmingham; Steven Koenig, Cardiovascular Innovation Institute; Toyoaki Murohara, Nagoya University Graduate School of Medicine; Benjamin L. Predmore, Emory University; Gabriel Gojon, NAN Laboratorios; Rui Wang, Lakehead University; Naveena Karusula, Emory University; Chad K. Nicholson, Emory University; John W Calvert, Emory University; David J. Lefer, Emory University
• Language: English
• Date: 2013-03-12
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013, Wolters Kluwer Health
• Final Published Version (URL): http://circ.ahajournals.org/content/127/10/1116.long
• Title of Journal or Parent Work: Circulation
• ISSN: 0009-7322
• Volume: 127
• Issue: 10
• Start Page: 1116
• End Page: 1127
• Grant/Funding Information: This work was also supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to Dr Wang.; This work was supported by grants from the National Heart, Lung, and Blood Institute (National Institutes of Health; 5R01HL092141, 5R01HL093579, 1U24HL 094373, and 1P20HL113452 to Dr Lefer and 5R01HL098481 to Dr Calvert).; We are also grateful for the generous funding support from the Carlyle Fraser Heart Center of Emory University Hospital Midtown.
• Keywords: hypertrophy; nitric oxide (NO); cyclic guanosine monophosphate (cGMP); vascular endothelial growth factor (VEGF); left ventricular function
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Rehabilitation and Therapy; Health Sciences, General

Abstract

Introduction Cystathionine gamma-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 (TAC) was performed in wild-type (WT), CSE knockout (KO), and cardiac specific CSE transgenic (CS-CSE Tg) mice. In addition, C57BL/6J or CSE KO mice received a novel–H2S donor (SG-1002). Mice were followed for 12 weeks using echocardiography. We observed a >60% reduction in myocardial and circulating H2S levels following TAC. CSE KO mice exhibited cardiac dilatation and dysfunction significantly greater than WT mice following TAC and CS-CSE Tg mice maintained cardiac structure and function following TAC. H2S therapy with SG-1002 resulted in cardioprotection during TAC via upregulation of the VEGF-Akt-eNOS-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 (eNOS) and increased NO bioavailability.