Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner. (April 2016)

• Record Type: Journal Article
• Authors: Shimizu, Yuuki; Nicholson, Chad K.; Lambert, Jonathan P.; Barr, Larry A.; Kuek, Nicholas; Herszenhaut, David; Tan, Lin; Murohara, Toyoaki; Hansen, Jason M.; Husain, Ahsan; Naqvi, Nawazish; Calvert, John W.
• Is Part Of: Circulation. Volume 9:Number 4(2016)
• Publication Date: 2016-04
• Subjects: heart failure -- hydrogen sulfide -- myocardial infarction -- Nrf2 -- proteasome; Heart failure -- Periodicals; 616.129005
• DOI: 10.1161/CIRCHEARTFAILURE.115.002368
• Languages: English
• ISSNs: 1941-3289

Abstract

Abstract : Background—: Therapeutic strategies aimed at increasing hydrogen sulfide (H2 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 H2 S and facilitator of H2 S-mediated cardioprotection after acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H2 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 H2 S in the form of sodium sulfide (Na2 S) displayed enhanced Nrf2 signaling, improved left ventricular function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na2 S therapy failed to provide protection against heart failure in Nrf2 KO mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2 S increased the expression of proteasome subunits, resulting in an increased proteasome activity and a reduction in the accumulation of damaged proteins. In contrast, Na2 S therapy failed to enhance the proteasome and failed to attenuate the accumulation of damaged proteins in Nrf2 KO mice. Additionally, Na2 S failed to improve cardiac function when the proteasome was inhibited. Conclusions—: These findings indicate that Na2 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. Abstract : Supplemental Digital Content is available in the text.