Transforming growth factor-β in myocardial disease.

Abstract

Transforming growth factor-β (TGFβ) 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 TGFβ from latent stores, through mechanisms involving proteases, integrins and specialized extracellular matrix (ECM) proteins. Activated TGFβ signals through the SMAD intracellular effectors or through non-SMAD cascades. In the infarcted heart, the anti-inflammatory and fibroblast-activating actions of TGFβ have an important role in repair; however, excessive or prolonged TGFβ signalling accentuates adverse remodelling, contributing to cardiac dysfunction. Cardiac pressure overload also activates TGFβ 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 TGFβ signalling in pressure-overloaded cardiomyocytes and fibroblasts can promote cardiac fibrosis and dysfunction. In the atria, TGFβ-mediated fibrosis can contribute to the pathogenic substrate for atrial fibrillation. Overactive or dysregulated TGFβ 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 TGFβ signalling in myocardial diseases, focusing on cellular targets and molecular mechanisms, and discussing challenges and opportunities for therapeutic translation.