Hydrogen Sulfide Mediates Cardioprotection Through Nrf2 Signaling

• Type of Material: Article
• Authors: John W Calvert, Emory University; Saurabh Jha, Albert Einstein College of Medicine; Susheel Gundewar, Albert Einstein College of Medicine; John W. Elrod, Cincinnati Children's Hospital Medical Center; Arun Ramachandran, Albert Einstein College of Medicine; Christopher B. Pattillo, LSU Health Sciences Center-Shreveport; Christopher G. Kevil, LSU Health Sciences Center-Shreveport; David J. Lefer, Emory University
• Language: English
• Date: 2009-08-14
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 American Heart Association, Inc. All rights reserved
• Final Published Version (URL): http://circres.ahajournals.org/content/105/4/365
• Title of Journal or Parent Work: Circulation Research
• ISSN: 0009-7330
• Volume: 105
• Issue: 4
• Start Page: 365
• End Page: 374
• Grant/Funding Information: Supported by grants from the NIH (2 RO1 HL-060849-09 and 5R01 HL-092141-01) and the American Diabetes Association (7-04-RA-59) to D.J.L and by a grant from the NIH (F32 DK 077380-01) to J.W.C. as well as funds from the Carlyle Fraser Heart Center of Emory University Hospital Midtown.
• Keywords: hydrogen sulfide; cardioprotection; antioxidant signaling; myocardial infarction; Nrf2
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Rationale The recent emergence of hydrogen sulfide (H2S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms. Objective The current study evaluated potential mechanisms of H2S-mediated cardioprotection using an in vivo model of pharmacological preconditioning (PC). Methods and Results H2S (100 μg/kg), or vehicle was administered to mice via an intravenous injection 24 hr prior to myocardial ischemia. Treated and untreated mice were then subjected to 45 min of myocardial ischemia followed by reperfusion for up to 24 hr, during which time the extent of myocardial infarction was evaluated, circulating troponin-I levels were measured, and the degree of oxidative stress was evaluated. In separate studies myocardial tissue was collected from treated and untreated mice during the early (30 min and 2hr) and late (24 hr) PC periods to evaluate potential cellular targets of H2S. Initial studies revealed that H2S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin-I levels, and oxidative stress. During the early PC period H2S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants, and increased the phosphorylation of PKCε and STAT-3. During the late PC period, H2S increased the expression of antioxidants (HO-1 and Trx1), increased the expression of HSP90, HSP70, Bcl-2, Bcl-xL, and COX-2 and also inactivated the pro-apoptogen Bad. Conclusions These results reveal that the cardioprotective effects of H2S are mediated in large part by a combination of antioxidant and anti-apoptotic signaling.