title: Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner.
abstract: BACKGROUND
  Therapeutic 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.
  
  
  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 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: 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.).
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: 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.).
authors.forename: Chad K
authors.initials: CK
authors.lastname: Nicholson
authors.affiliation: 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.).
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: 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.).
authors.forename: Larry A
authors.initials: LA
authors.lastname: Barr
authors.affiliation: 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.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kuek
authors.affiliation: 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.).
authors.forename: David
authors.initials: D
authors.lastname: Herszenhaut
authors.affiliation: 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.).
authors.forename: Lin
authors.initials: L
authors.lastname: Tan
authors.affiliation: 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.).
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: 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.).
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hansen
authors.affiliation: 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.).
authors.forename: Ahsan
authors.initials: A
authors.lastname: Husain
authors.affiliation: 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.).
authors.forename: Nawazish
authors.initials: N
authors.lastname: Naqvi
authors.affiliation: 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.). jcalver@emory.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002317:Cardiovascular Agents; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013440:Sulfides; D046988:Proteasome Endopeptidase Complex; C033479:sodium sulfide; D006862:Hydrogen Sulfide
keywords: Nrf2; heart failure; hydrogen sulfide; myocardial infarction; proteasome