Published online before print October 22, 2007, doi: 10.1161/CIRCULATIONAHA.107.704197
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(Circulation. 2007;116:2127-2138.)
© 2007 American Heart Association, Inc.
Molecular Cardiology |
Essential Role of Smad3 in Infarct Healing and in the Pathogenesis of Cardiac Remodeling
From the Section of Cardiovascular Sciences (M.B., G.R., H.J.K., M.D., A.R., G.T., N.G.F.), Baylor College of Medicine, Houston, Tex, and Department of Pharmacology and Cancer Biology (X.-F.W.), Duke University, Durham, NC.
Correspondence to Nikolaos G. Frangogiannis, MD, Section of Cardiovascular Sciences, One Baylor Plaza M/S BCM620, Baylor College of Medicine, Houston, TX 77030. E-mail ngf{at}bcm.tmc.edu
Received March 19, 2007; accepted August 17, 2007.
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-ß/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-ß–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-ß 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.
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