Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner

• Type of Material: Article
• Authors: Yuuki Shimizu, Emory University; Chad K. Nicholson, Emory University; Jonathan P. Lambert, Emory University; Larry A. Barr, Emory University; Nicholas Kuek, Emory University; David Herszenhaut, Emory University; Lin Tan, Emory University; Toyoaki Murohara, Nagoya University; Jason M. Hansen, Emory University; Ahsan Husain, Emory University; Nawazish Naqvi, Emory University; John Calvert, Emory University
• Language: English
• Date: 2016-04-07
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCHEARTFAILURE.115.002368
• Title of Journal or Parent Work: Circulation: Heart Failure
• ISSN: 1941-3289
• Volume: 9
• Issue: 4
• Start Page: e002368
• End Page: e002368
• Grant/Funding Information: This work was also supported by funding from the Carlyle Fraser Heart Center of Emory University Hospital Midtown to Dr Calvert and the Banyu Fellowship program sponsored by Banyu Life Science Foundation International to Dr Shimizu.; Supported by grants from the National Institutes of Health (NIH; 5R01HL098481-05 to Dr Calvert) and the American Heart Association (AHA; 15POST25610016 to Dr Shimizu).
• Keywords: hydrogen sulfide; PROTEIN-KINASE; proteasome; REPERFUSION INJURY; PATHWAY; Cardiovascular System & Cardiology; MICE; Science & Technology; Life Sciences & Biomedicine; ANTIOXIDANT RESPONSE; heart failure; CELL-SURVIVAL; myocardial infarction; GENE-EXPRESSION; Cardiac & Cardiovascular Systems; NRF2; CARDIAC DYSFUNCTION; HYDROGEN-SULFIDE; Nrf2
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background - Therapeutic strategies aimed at increasing hydrogen sulfide (H 2 S) levels exert cytoprotective effects in various models of cardiovascular injury. However, the underlying mechanism(s) responsible for this protection remain to be fully elucidated. Nuclear factor E2-related factor 2 (Nrf2) is a cellular target of H 2 S and facilitator of H 2 S-mediated cardioprotection after acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H 2 S therapy in the setting of heart failure. Methods and Results - Mice (12 weeks of age) deficient in Nrf2 (Nrf2 KO; C57BL/6J background) and wild-type littermates were subjected to ischemic-induced heart failure. Wild-type mice treated with H 2 S in the form of sodium sulfide (Na 2 S) displayed enhanced Nrf2 signaling, improved left ventricular function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na 2 S therapy failed to provide protection against heart failure in Nrf2 KO mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na 2 S increased the expression of proteasome subunits, resulting in an increased proteasome activity and a reduction in the accumulation of damaged proteins. In contrast, Na 2 S therapy failed to enhance the proteasome and failed to attenuate the accumulation of damaged proteins in Nrf2 KO mice. Additionally, Na 2 S failed to improve cardiac function when the proteasome was inhibited. Conclusions - These findings indicate that Na 2 S therapy enhances proteasomal activity and function during the development of heart failure in an Nrf2-dependent manner and that this enhancement leads to attenuation in cardiac dysfunction.