• Circ Heart Fail · Apr 2016

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

    • Yuuki Shimizu, Chad K Nicholson, Jonathan P Lambert, Larry A Barr, Nicholas Kuek, David Herszenhaut, Lin Tan, Toyoaki Murohara, Jason M Hansen, Ahsan Husain, Nawazish Naqvi, and John W Calvert.
    • From the Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center (Y.S., C.K.N., J.P.L., L.A.B., N.K., D.H., J.W.C.), Department of Medicine, Division of Cardiology (L.T., A.H., N.N.), and Department of Pediatrics (J.M.H.), Emory University School of Medicine, Atlanta, GA; and Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.M.).
    • Circ Heart Fail. 2016 Apr 1; 9 (4): e002368.

    BackgroundTherapeutic strategies aimed at increasing hydrogen sulfide (H2S) 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 H2S and facilitator of H2S-mediated cardioprotection after acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H2S therapy in the setting of heart failure.Methods And ResultsMice (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 H2S in the form of sodium sulfide (Na2S) displayed enhanced Nrf2 signaling, improved left ventricular function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na2S therapy failed to provide protection against heart failure in Nrf2 KO mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S increased the expression of proteasome subunits, resulting in an increased proteasome activity and a reduction in the accumulation of damaged proteins. In contrast, Na2S therapy failed to enhance the proteasome and failed to attenuate the accumulation of damaged proteins in Nrf2 KO mice. Additionally, Na2S failed to improve cardiac function when the proteasome was inhibited.ConclusionsThese findings indicate that Na2S 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.© 2016 American Heart Association, Inc.

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