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

Abstract

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".

Figure 1

TGF-β signaling pathways. TGF-β transduces its signal through Smad-dependent and Smad-independent pathways.

Figure 2

The cellular effects of TGF-β. TGF-β exerts pleiotropic effects on all cell types involved in cardiac injury, repair and remodeling.

Figure 3

The role of TGF-β in hypertrophy, fibrosis and post-infarction cardiac remodeling. A: TGF-β transduces hypertrophic signals in cardiomyocytes and induces myofibroblast transdifferentiation, while promoting matrix deposition and preservation. Although TGF-β inhibition in the pressure-overloaded ventricle may attenuate hypertrophy and reduce fibrosis protecting from diastolic dysfunction, complete loss of TGF-β signaling may result in unopposed matrix degradation, cardiac dilation and systolic dysfunction. B: In the infarcted heart TGF-β may serve as the “master switch” that regulates transition from the inflammatory phase to scar formation. TGF-β suppresses inflammatory mediator synthesis by macrophages while enhancing myofibroblast transdifferentiation and matrix deposition. Thus, timing is a crucial determinant of outcome in pharmacologic interventions targeting the TGF-β system following myocardial infarction.