title: Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function.
abstract: BACKGROUND
  Thioredoxin 2 (Trx2) is a key mitochondrial protein that regulates cellular redox and survival by suppressing mitochondrial reactive oxygen species generation and by inhibiting apoptosis stress kinase-1 (ASK1)-dependent apoptotic signaling. To date, the role of the mitochondrial Trx2 system in heart failure pathogenesis has not been investigated.
  
  
  RESULTS
  Western blot and histological analysis revealed that Trx2 protein expression levels were reduced in hearts from patients with dilated cardiomyopathy, with a concomitant increase in ASK1 phosphorylation/activity. Cardiac-specific Trx2 knockout mice develop spontaneous dilated cardiomyopathy at 1 month of age with increased heart size, reduced ventricular wall thickness, and a progressive decline in left ventricular contractile function, resulting in mortality due to heart failure by ≈4 months of age. The progressive decline in cardiac function observed in cardiac-specific Trx2 knockout mice was accompanied by the disruption of mitochondrial ultrastructure, mitochondrial membrane depolarization, increased mitochondrial reactive oxygen species generation, and reduced ATP production, correlating with increased ASK1 signaling and increased cardiomyocyte apoptosis. Chronic administration of a highly selective ASK1 inhibitor improved cardiac phenotype and reduced maladaptive left ventricular remodeling with significant reductions in oxidative stress, apoptosis, fibrosis, and cardiac failure. Cellular data from Trx2-deficient cardiomyocytes demonstrated that ASK1 inhibition reduced apoptosis and reduced mitochondrial reactive oxygen species generation.
  
  
  CONCLUSIONS
  Our data support an essential role for mitochondrial Trx2 in preserving cardiac function by suppressing mitochondrial reactive oxygen species production and ASK1-dependent apoptosis. Inhibition of ASK1 represents a promising therapeutic strategy for the treatment of dilated cardiomyopathy and heart failure.
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Qunhua
authors: Q
authors: Huang
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Huanjiao Jenny
authors: HJ
authors: Zhou
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Haifeng
authors: H
authors: Zhang
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Yan
authors: Y
authors: Huang
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Ford
authors: F
authors: Hinojosa-Kirschenbaum
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Peidong
authors: P
authors: Fan
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Lina
authors: L
authors: Yao
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Luiz
authors: L
authors: Belardinelli
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: George
authors: G
authors: Tellides
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Frank J
authors: FJ
authors: Giordano
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
authors: Grant R
authors: GR
authors: Budas
authors: From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.). wang.min@yale.edu.
authors: Wang
authors: W
authors: Min
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013879:Thioredoxins / Q000096:biosynthesis*
chemical_list: D017382:Reactive Oxygen Species; C516112:Txn2 protein, mouse; D013879:Thioredoxins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: ASK1/MAPKKK5; cardiomyopathy, dilated; heart failure; mitochondria; thioredoxins
references: Mol Cell Biol. 2005 Mar;25(5):1980-8
references: 15713651
references: Circ Res. 2004 Nov 12;95(10):957-70
references: 15539639
references: Free Radic Biol Med. 2012 Sep 15;53(6):1252-63
references: 22841758
references: J Am Heart Assoc. 2012 Oct;1(5):e002360
references: 23316291
references: J Mol Cell Cardiol. 2009 Jun;46(6):811-20
references: 19281816
references: Circulation. 2010 Mar 16;121(10):1244-55
references: 20194885
references: Antioxid Redox Signal. 2007 Jun;9(6):679-87
references: 17419666
references: J Mol Cell Cardiol. 2006 Nov;41(5):762-73
references: 17007870
references: Biochem J. 2011 Apr 15;435(2):297-312
references: 21726199
references: J Mol Cell Cardiol. 2012 Jan;52(1):48-61
references: 21964191
references: J Mol Cell Cardiol. 2003 Jun;35(6):695-704
references: 12788387
references: Cardiovasc Res. 2006 Jul 15;71(2):208-15
references: 16631149
references: Cell. 1999 Jul 9;98(1):115-24
references: 10412986
references: Circulation. 2005 May 31;111(21):2837-49
references: 15927992
references: Eur Heart J. 2011 May;32(9):1121-33
references: 21247928
references: Antioxid Redox Signal. 2013 Apr 1;18(10):1165-207
references: 22607099
references: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11471-6
references: 15277664
references: Free Radic Biol Med. 2011 Apr 1;50(7):777-93
references: 21236334
references: J Biol Chem. 2000 Aug 25;275(34):26576-81
references: 10849426
references: Heart Lung Circ. 2004 Jun;13(2):132-8
references: 16352183
references: Dev Biol. 1996 Aug 25;178(1):179-85
references: 8812119
references: Antioxid Redox Signal. 2000 Winter;2(4):811-20
references: 11213485
references: Arch Mal Coeur Vaiss. 2003 Mar;96(3):214-21
references: 12722552
references: Annu Rev Pathol. 2009;4:71-95
references: 18754744
references: Circulation. 2003 Dec 16;108(24):3036-41
references: 14638549
references: Circulation. 2011 Dec 20;124(25):2892-902
references: 22144571
references: Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
references: 16936699
references: Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):495-502
references: 19150880
references: Congest Heart Fail. 2002 May-Jun;8(3):132-40
references: 12045381
references: Am J Pathol. 2007 Mar;170(3):1108-20
references: 17322393
references: Mol Cell Biol. 2003 Feb;23(3):916-22
references: 12529397
references: Anticancer Agents Med Chem. 2014;14(7):946-54
references: 24913775
references: Biochem J. 2010 Jan 15;425(2):313-25
references: 20025614
references: Cell. 2008 Jun 13;133(6):978-93
references: 18555775
references: J Cardiovasc Pharmacol. 2012 Sep;60(3):276-82
references: 22635076
references: J Clin Invest. 2005 Mar;115(3):500-8
references: 15765131
references: J Am Coll Cardiol. 1998 Nov;32(5):1454-9
references: 9809962
references: EMBO J. 2002 Apr 2;21(7):1695-703
references: 11927553
references: Circ Res. 2014 Feb 14;114(4):626-36
references: 24366168
references: J Cell Biol. 1990 Dec;111(6 Pt 1):2427-36
references: 2277065
references: Mol Cell Biol. 2004 Nov;24(21):9414-23
references: 15485910
references: Circ Res. 2004 Jun 11;94(11):1483-91
references: 15117824
references: J Clin Invest. 2003 Nov;112(9):1395-406
references: 14597765
references: J Clin Invest. 2003 May;111(10):1497-504
references: 12750399
references: Clin Exp Pharmacol Physiol. 2004 May-Jun;31(5-6):289-94
references: 15191400