The role of transforming growth factor (TGF)-β in the infarcted myocardium

Abstract

The adult mammalian heart has negligible regenerative capacity. Following myocardial infarction, sudden necrosis of cardiomyocytes triggers an intense inflammatory reaction that clears the wound from dead cells and matrix debris, while activating a reparative program. A growing body of evidence suggests that members of the transforming growth factor (TGF)-β family critically regulate the inflammatory and reparative response following infarction. Although all three TGF-β isoforms (TGF-β1, -β2 and -β3) are markedly upregulated in the infarcted myocardium, information on isoform-specific actions is limited. Experimental studies have suggested that TGF-β exerts a wide range of actions on cardiomyocytes, fibroblasts, immune cells, and vascular cells. The findings are often conflicting, reflecting the context-dependence of TGF-β-mediated effects; conclusions are often based exclusively on in vitro studies and on associative evidence. TGF-β has been reported to modulate cardiomyocyte survival responses, promote monocyte recruitment, inhibit macrophage pro-inflammatory gene expression, suppress adhesion molecule synthesis by endothelial cells, promote myofibroblast conversion and extracellular matrix synthesis, and mediate both angiogenic and angiostatic effects. This review manuscript discusses our understanding of the cell biological effects of TGF-β in myocardial infarction. We discuss the relative significance of downstream TGF-β-mediated Smad-dependent and -independent pathways, and the risks and challenges of therapeutic TGF-β targeting. Considering the high significance of TGF-β-mediated actions in vivo, study of cell-specific effects and dissection of downstream signaling pathways are needed in order to design safe and effective therapeutic approaches.

Keywords: Transforming growth factor-beta (TGF-β); cardiac remodeling; cardiomyocyte; fibroblast; inflammation; myocardial infarction.

Figure 1

The cell biological actions of TGF-β in the infarcted myocardium. TGF-β may exert a wide range of actions on all cell types involved in injury, repair and remodeling of the infarcted heart. TGF-β may modulate survival pathways in cardiomyocytes, promote mononuclear cell chemotaxis, exert anti-inflammatory actions on macrophages, suppress endothelial cell adhesion molecule synthesis, modulate lymphocyte phenotype, promote myofibroblast conversion and activation, and regulate angiogenesis and vascular maturation symbols. Mo, monocyte; N, neutrophil; L, lymphocyte; Ma, macrophage; CM, cardiomyocyte; EC, endothelial cell; F, fibroblast; MF, myofibroblast; P, pericyte; TGF-β, transforming growth factor-beta.