Transforming growth factor (TGF)-β signaling in cardiac remodeling

Myocardial TGF-beta expression is upregulated in experimental models of myocardial infarction and cardiac hypertrophy, and in patients with dilated or hypertrophic cardiomyopathy. Through its effects on cardiomyocytes, mesenchymal and immune cells, TGF-beta plays an important role in the pathogenesis of cardiac remodeling and fibrosis. TGF-beta overexpression in the mouse heart is associated with fibrosis and hypertrophy. Endogenous TGF-beta plays an important role in the pathogenesis of cardiac fibrotic and hypertrophic remodeling, and modulates matrix metabolism in the pressure-overloaded heart. In the infarcted heart, TGF-beta deactivates inflammatory macrophages, while promoting myofibroblast transdifferentiation and matrix synthesis through Smad3-dependent pathways. Thus, TGF-beta may serve as the master switchThis article is part of a special issue entitled Key Signaling Molecules in Hypertrophy and Heart Failure, for the transition of the infarct from the inflammatory phase to formation of the scar. Because of its crucial role in cardiac remodeling, the TGF-beta system may be a promising therapeutic target for patients with heart failure. However, efforts to translate these concepts into therapeutic strategies, in order to prevent cardiac hypertrophy and fibrosis, are hampered by the complex, pleiotropic and diverse effects of TGF-beta signaling, by concerns regarding deleterious actions of TGF-beta inhibition and by the possibility of limited benefit in patients receiving optimal treatment with ACE inhibitors and beta-adrenergic blockers. Dissection of the pathways responsible for specific TGF-beta-mediated actions and understanding of cell-specific actions of TGF-beta are needed to design optimal therapeutic strategies. This article is part of a special issue entitled Key Signaling Molecules in Hypertrophy and Heart Failure. (C) 2010 Elsevier Ltd. All rights reserved.