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

Myocardial TGF-β 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-β plays an important role in the pathogenesis of cardiac remodeling and fibrosis. TGF-β overexpression in the mouse heart is associated with fibrosis and hypertrophy. Endogenous TGF-β 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-β deactivates inflammatory macrophages, while promoting myofibroblast transdifferentiation and matrix synthesis through Smad3-dependent pathways. Thus, TGF-β 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-β 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-β signaling, by concerns regarding deleterious actions of TGF-β inhibition and by the possibility of limited benefit in patients receiving optimal treatment with ACE inhibitors and β-adrenergic blockers. Dissection of the pathways responsible for specific TGF-β-mediated actions and understanding of cell-specific actions of TGF-β are needed to design optimal therapeutic strategies. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure”.

Research Highlights
► Introduction: The biology of TGF-β.
► Cellular effects of TGF-β.
► Expression and regulation of TGF-β in animal models of heart failure.
► The role of TGF-β signaling in the failing heart.
► The relation between TGF-β and the renin-angiotensin system (RAS).
► Increased expression of TGF-β in human cardiomyopathy.
► Targeting the TGF-β system in the failing heart.
► Future directions.