title: The AP-1 transcription factor c-Jun prevents stress-imposed maladaptive remodeling of the heart.
abstract: Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hypertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload.
authors.affiliation: Institute of Cell Biology, Eidgenössische Technische Hochschule Zurich (ETHZ), Zurich, Switzerland.
authors.forename: Renata
authors.initials: R
authors.lastname: Windak
authors.forename: Julius
authors.initials: J
authors.lastname: Müller
authors.forename: Allison
authors.initials: A
authors.lastname: Felley
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sumara
authors.forename: Romeo
authors.initials: R
authors.lastname: Ricci
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D006321:Heart / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011312:Pressure; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1
references.citation: Mol Cell. 1998 Nov;2(5):559-69
references.pmid: 9844629
references.citation: Circulation. 2004 Sep 28;110(13):1806-13
references.pmid: 15381649
references.citation: J Clin Invest. 2002 Apr;109(7):849-55
references.pmid: 11927610
references.citation: Circ Res. 2005 Aug 19;97(4):380-90
references.pmid: 16037568
references.citation: Cell. 1999 Sep 3;98(5):555-8
references.pmid: 10490095
references.citation: J Clin Invest. 2003 May;111(10):1475-86
references.pmid: 12750397
references.citation: Nat Cell Biol. 2002 May;4(5):E131-6
references.pmid: 11988758
references.citation: Physiol Rev. 2007 Oct;87(4):1285-342
references.pmid: 17928585
references.citation: Annu Rev Physiol. 1997;59:551-71
references.pmid: 9074777
references.citation: J Cell Commun Signal. 2013 Mar;7(1):31-47
references.pmid: 23208610
references.citation: J Biol Chem. 1995 Dec 22;270(51):30593-603
references.pmid: 8530495
references.citation: Cell. 2002 Sep 20;110(6):737-49
references.pmid: 12297047
references.citation: Cell Metab. 2009 Jun;9(6):512-24
references.pmid: 19490906
references.citation: J Exp Med. 2008 Feb 18;205(2):295-303
references.pmid: 18208976
references.citation: Circ Res. 2009 Jan 2;104(1):e1-7
references.pmid: 19038863
references.citation: J Mol Cell Cardiol. 2003 Dec;35(12):1385-94
references.pmid: 14654364
references.citation: Int Rev Cytol. 2005;246:31-58
references.pmid: 16164966
references.citation: Circ Res. 2002 Oct 4;91(7):640-7
references.pmid: 12364393
references.citation: Genes Dev. 2002 Jan 1;16(1):46-57
references.pmid: 11782444
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12283-8
references.pmid: 11593045
references.citation: EMBO J. 1999 Jan 4;18(1):188-97
references.pmid: 9878062
references.citation: J Mol Cell Cardiol. 2000 Feb;32(2):187-95
references.pmid: 10722796
references.citation: Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2369-75
references.pmid: 14764439
references.citation: Hypertension. 2002 Jan;39(1):81-6
references.pmid: 11799083
references.citation: Genes Dev. 2005 Jan 15;19(2):208-13
references.pmid: 15655111
references.citation: Cell Biochem Biophys. 2006;45(3):317-37
references.pmid: 16845177
references.citation: EMBO J. 2003 Oct 1;22(19):5079-89
references.pmid: 14517246
references.citation: Cell Signal. 2010 May;22(5):809-20
references.pmid: 20074638
references.citation: Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
references.pmid: 16936699
references.citation: Circ Res. 2004 May 28;94(10):1279-89
references.pmid: 15166115
references.citation: J Clin Invest. 2005 Mar;115(3):518-26
references.pmid: 15765133
references.citation: EMBO J. 2000 Dec 1;19(23):6341-50
references.pmid: 11101507
references.citation: J Biol Chem. 1996 May 3;271(18):10827-33
references.pmid: 8631897
references.citation: PLoS One. 2012;7(12):e52120
references.pmid: 23284892
references.citation: FASEB J. 2003 Apr;17(6):749-51
references.pmid: 12594183
references.citation: Mol Cell Biol. 1992 Jan;12(1):292-301
references.pmid: 1530876
references.citation: Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1291-302
references.pmid: 21186275
references.citation: Circ J. 2011;75(8):1811-8
references.pmid: 21747195
references.citation: J Biol Chem. 1990 Mar 5;265(7):3595-8
references.pmid: 2105950
references.citation: Mol Cell Biol. 2005 Feb;25(3):865-78
references.pmid: 15657416
references.citation: Circ Res. 2009 Jan 30;104(2):170-8, 6p following 178
references.pmid: 19096030
references.citation: EMBO J. 2002 Apr 2;21(7):1782-90
references.pmid: 11927562
references.citation: Nat Rev Cancer. 2003 Nov;3(11):859-68
references.pmid: 14668816
references.citation: N Engl J Med. 2008 Mar 27;358(13):1370-80
references.pmid: 18367740
references.citation: Nature. 2001 Mar 1;410(6824):37-40
references.pmid: 11242034
references.citation: Ann Med. 2001 Dec;33(9):611-22
references.pmid: 11817656
references.citation: Nat Med. 2007 Aug;13(8):962-9
references.pmid: 17632525
references.citation: Circulation. 1998 Oct 27;98(17):1728-34
references.pmid: 9788826
references.citation: Mol Biol Rep. 2013 Feb;40(2):1677-83
references.pmid: 23076534
references.citation: Genes Dev. 2000 Nov 1;14(21):2695-700
references.pmid: 11069886
references.citation: Development. 2007 Dec;134(23):4131-40
references.pmid: 17959722
references.citation: Nat Med. 2004 May;10(5):467-74
references.pmid: 15122248
references.citation: Annu Rev Physiol. 1991;53:179-200
references.pmid: 2042959
references.citation: J Cell Biol. 1999 May 31;145(5):1049-61
references.pmid: 10352021
references.citation: J Clin Invest. 2002 Jul;110(2):271-9
references.pmid: 12122119
references.citation: Biochem Biophys Res Commun. 2006 May 19;343(4):1060-6
references.pmid: 16579967
references.citation: Trends Mol Med. 2003 Apr;9(4):177-82
references.pmid: 12727144
references.citation: J Mol Cell Cardiol. 1996 Apr;28(4):735-42
references.pmid: 8732501
references.citation: Basic Res Cardiol. 1992;87 Suppl 2:33-48
references.pmid: 1284369
references.citation: J Mol Cell Cardiol. 2011 Jun;50(6):928-38
references.pmid: 21376054
references.citation: Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8277-81
references.pmid: 1832775
references.citation: Annu Rev Physiol. 1993;55:77-95
references.pmid: 8466192
references.citation: J Biol Chem. 1992 Dec 15;267(35):25535-40
references.pmid: 1460048
references.citation: Genes Dev. 2005 May 15;19(10):1175-87
references.pmid: 15870258
references.citation: Circulation. 2005 Sep 6;112(10):1470-7
references.pmid: 16129800
references.citation: Am J Physiol. 1992 Jun;262(6 Pt 2):H1861-6
references.pmid: 1535758
references.citation: J Neurosci. 2003 Oct 8;23(27):9116-22
references.pmid: 14534245
references.citation: Eur J Clin Invest. 2002 May;32(5):295-303
references.pmid: 12027867
references.citation: Cell. 2003 Jan 24;112(2):181-92
references.pmid: 12553907
references.citation: Circulation. 1991 Sep;84(3):1256-65
references.pmid: 1832094
references.citation: Nat Med. 2000 Feb;6(2):183-8
references.pmid: 10655107