Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling

Marcin Bujak, Guofeng Ren, Hyuk Jung Kweon, Marcin Dobaczewski, Anilkumar Reddy, George Taffet, Xiao Fan Wang, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

BACKGROUND - Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-β/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses. METHODS AND RESULTS - We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3 mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-β-mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-β responses. CONCLUSIONS - Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.

Original languageEnglish (US)
Pages (from-to)2127-2138
Number of pages12
JournalCirculation
Volume116
Issue number19
DOIs
StatePublished - Nov 2007
Externally publishedYes

Fingerprint

Transforming Growth Factors
Tenascin
Myocardium
Wild Animals
Collagen Type III
Myofibroblasts
Neutrophil Infiltration
Chemokines
Genes
Cicatrix
Fibrosis
Collagen
Fibroblasts
Myocardial Infarction
Inflammation
Wounds and Injuries
Therapeutics

Keywords

  • Infarction
  • Inflammation
  • Pathology
  • Remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. / Bujak, Marcin; Ren, Guofeng; Kweon, Hyuk Jung; Dobaczewski, Marcin; Reddy, Anilkumar; Taffet, George; Wang, Xiao Fan; Frangogiannis, Nikolaos G.

In: Circulation, Vol. 116, No. 19, 11.2007, p. 2127-2138.

Research output: Contribution to journalArticle

Bujak, M, Ren, G, Kweon, HJ, Dobaczewski, M, Reddy, A, Taffet, G, Wang, XF & Frangogiannis, NG 2007, 'Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling', Circulation, vol. 116, no. 19, pp. 2127-2138. https://doi.org/10.1161/CIRCULATIONAHA.107.704197
Bujak, Marcin ; Ren, Guofeng ; Kweon, Hyuk Jung ; Dobaczewski, Marcin ; Reddy, Anilkumar ; Taffet, George ; Wang, Xiao Fan ; Frangogiannis, Nikolaos G. / Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. In: Circulation. 2007 ; Vol. 116, No. 19. pp. 2127-2138.
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AU - Bujak, Marcin

AU - Ren, Guofeng

AU - Kweon, Hyuk Jung

AU - Dobaczewski, Marcin

AU - Reddy, Anilkumar

AU - Taffet, George

AU - Wang, Xiao Fan

AU - Frangogiannis, Nikolaos G.

PY - 2007/11

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N2 - BACKGROUND - Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-β/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses. METHODS AND RESULTS - We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3 mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-β-mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-β responses. CONCLUSIONS - Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.

AB - BACKGROUND - Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-β/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses. METHODS AND RESULTS - We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3 mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-β-mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-β responses. CONCLUSIONS - Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.

KW - Infarction

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KW - Pathology

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