Transforming growth factor-β in myocardial disease

Transforming growth factor-beta (TGF beta) isoforms are upregulated and activated in myocardial diseases and have an important role in cardiac repair and remodelling, regulating the phenotype and function of cardiomyocytes, fibroblasts, immune cells and vascular cells. Cardiac injury triggers the generation of bioactive TGF beta from latent stores, through mechanisms involving proteases, integrins and specialized extracellular matrix (ECM) proteins. Activated TGF beta signals through the SMAD intracellular effectors or through non-SMAD cascades. In the infarcted heart, the anti-inflammatory and fibroblast-activating actions of TGF beta have an important role in repair; however, excessive or prolonged TGF beta signalling accentuates adverse remodelling, contributing to cardiac dysfunction. Cardiac pressure overload also activates TGF beta cascades, which initially can have a protective role, promoting an ECM-preserving phenotype in fibroblasts and preventing the generation of injurious, pro-inflammatory ECM fragments. However, prolonged and overactive TGF beta signalling in pressure-overloaded cardiomyocytes and fibroblasts can promote cardiac fibrosis and dysfunction. In the atria, TGF beta-mediated fibrosis can contribute to the pathogenic substrate for atrial fibrillation. Overactive or dysregulated TGF beta responses have also been implicated in cardiac ageing and in the pathogenesis of diabetic, genetic and inflammatory cardiomyopathies. This Review summarizes the current evidence on the role of TGF beta signalling in myocardial diseases, focusing on cellular targets and molecular mechanisms, and discussing challenges and opportunities for therapeutic translation. In this Review, Frangogiannis summarizes the current evidence on the role of TGF beta signalling in myocardial diseases, focusing on TGF beta functions in cardiac pathophysiology and its cellular actions and molecular effectors, and discusses challenges and opportunities for therapeutic interventions targeting the TGF beta system in heart disease.