Smad-dependent pathways in the infarcted and failing heart

Abstract

In infarcted and failing hearts, TGF-β superfamily members play an important role in regulation of inflammatory, reparative, fibrogenic, and hypertrophic responses through activation of Smad-dependent and Smad-independent cascades. This review manuscript discusses the mechanisms of regulation and role of Smad pathways in myocardial infarction and in heart failure. Cardiomyocyte-specific Smad1 activation exerts protective anti-apoptotic actions following ischemia/reperfusion. In contrast, the role of the Smad1/5/8 cascade in reparative, immune, and vascular cells infiltrating the infarcted heart is unknown. Smad3, but not Smad2 is implicated in repair of the infarcted heart, by activating reparative myofibroblasts and by promoting anti-inflammatory transition in macrophages. However, prolonged activation of Smad3 may promote adverse remodeling and fibrosis. The inhibitory Smad, Smad7 restrains TGF-β-induced fibroblast activation, but also exerts TGF-independent actions through inhibition of receptor tyrosine kinase signaling. Cell-specific approaches targeting Smad pathways may hold therapeutic promise in myocardial infarction and in heart failure.