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

• 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
• Journal Title: Circulation: Heart Failure
• Volume: Volume 9, Number 4
• Publisher: American Heart Association | 2016-04-07, Pages e002368-e002368
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1161/CIRCHEARTFAILURE.115.002368
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Cardiovascular System & Cardiology; heart failure; hydrogen sulfide; myocardial infarction; Nrf2; proteasome; HYDROGEN-SULFIDE; CARDIAC DYSFUNCTION; ANTIOXIDANT RESPONSE; REPERFUSION INJURY; GENE-EXPRESSION; PROTEIN-KINASE; CELL-SURVIVAL; NRF2; PATHWAY; MICE

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.