title: Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction.
abstract: Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-β signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-β signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-β signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA. ttsuda@nemours.org
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsuda
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Joyce
authors.forename: Dessislava
authors.initials: D
authors.lastname: Markova
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Hangxiang
authors.initials: H
authors.lastname: Zhang
authors.forename: Yaqun
authors.initials: Y
authors.lastname: Zou
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Thomas
authors.initials: T
authors.lastname: Miller
authors.forename: Walter
authors.initials: W
authors.lastname: Koch
authors.forename: Xingliang
authors.initials: X
authors.lastname: Ma
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009206:Myocardium / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; C084612:fibulin 2; D000804:Angiotensin II
references.citation: Dev Dyn. 2001 Sep;222(1):89-100
references.pmid: 11507771
references.citation: Mol Cell Biol. 2008 Feb;28(3):1061-7
references.pmid: 18070922
references.citation: Circulation. 2007 Nov 6;116(19):2127-38
references.pmid: 17967775
references.citation: Physiol Genomics. 2008 Jul 15;34(2):162-84
references.pmid: 18460641
references.citation: Cardiovasc Res. 2005 Apr 1;66(1):22-32
references.pmid: 15769445
references.citation: J Cell Biol. 1993 Dec;123(5):1269-77
references.pmid: 8245130
references.citation: J Biol Chem. 2005 May 13;280(19):18871-80
references.pmid: 15677465
references.citation: J Mol Biol. 1995 Dec 15;254(5):892-9
references.pmid: 7500359
references.citation: Curr Opin Cell Biol. 1999 Oct;11(5):634-40
references.pmid: 10508658
references.citation: Cardiovasc Res. 2003 Oct 1;59(4):926-33
references.pmid: 14553832
references.citation: Science. 2000 Aug 18;289(5482):1197-202
references.pmid: 10947988
references.citation: Cardiovasc Res. 1999 Nov;44(2):232-41
references.pmid: 10690298
references.citation: J Biol Chem. 2009 Jun 19;284(25):16872-16881
references.pmid: 19349279
references.citation: Cardiovasc Res. 2007 May 1;74(2):184-95
references.pmid: 17109837
references.citation: Exp Cell Res. 1996 Jan 10;222(1):111-6
references.pmid: 8549652
references.citation: Birth Defects Res C Embryo Today. 2004 Mar;72(1):37-50
references.pmid: 15054903
references.citation: Nat Med. 2000 May;6(5):556-63
references.pmid: 10802712
references.citation: Circulation. 1999 Nov 16;100(20):2093-9
references.pmid: 10562266
references.citation: Glycoconj J. 2002 May-Jun;19(4-5):257-62
references.pmid: 12975603
references.citation: Am J Physiol Heart Circ Physiol. 2003 Sep;285(3):H1229-35
references.pmid: 12775562
references.citation: Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1847-60
references.pmid: 17158653
references.citation: Circulation. 2008 Mar 11;117(10):1269-76
references.pmid: 18299507
references.citation: J Exp Med. 2009 Jan 16;206(1):113-23
references.pmid: 19103879
references.citation: J Mol Cell Cardiol. 2010 Mar;48(3):504-11
references.pmid: 19631653
references.citation: Mol Cancer Res. 2007 Oct;5(10):1041-51
references.pmid: 17951404
references.citation: Nat Rev Mol Cell Biol. 2003 Jun;4(6):479-89
references.pmid: 12778127
references.citation: Mol Genet Metab. 2000 Sep-Oct;71(1-2):418-35
references.pmid: 11001836
references.citation: Cardiovasc Res. 2006 Feb 15;69(3):755-63
references.pmid: 16409997
references.citation: Cardiovasc Res. 2004 Oct 1;64(1):24-31
references.pmid: 15364610
references.citation: J Cell Biochem. 2007 Jun 1;101(3):695-711
references.pmid: 17226767
references.citation: Circulation. 2003 Sep 16;108(11):1395-403
references.pmid: 12975244
references.citation: J Card Fail. 2002 Dec;8(6 Suppl):S344-8
references.pmid: 12555143
references.citation: Circ Res. 2007 Aug 3;101(3):313-21
references.pmid: 17569887
references.citation: Pediatr Crit Care Med. 2007 Jan;8(1):40-6
references.pmid: 17149150