Abstract
The members of the transforming growth factor β (TGF-β) superfamily are essential regulators of cell differentiation, phenotype and function, and have been implicated in the pathogenesis of many diseases. Myocardial infarction is associated with induction of several members of the superfamily, including TGF-β1, TGF-β2, TGF-β3, bone morphogenetic protein (BMP)-2, BMP-4, BMP-10, growth differentiation factor (GDF)-8, GDF-11 and activin A. This manuscript reviews our current knowledge on the patterns and mechanisms of regulation and activation of TGF-β superfamily members in the infarcted heart, and discusses their cellular actions and downstream signaling mechanisms. In the infarcted heart, TGF-β isoforms modulate cardiomyocyte survival and hypertrophic responses, critically regulate immune cell function, activate fibroblasts, and stimulate a matrix-preserving program. BMP subfamily members have been suggested to exert both pro- and anti-inflammatory actions and may regulate fibrosis. Members of the GDF subfamily may also modulate survival and hypertrophy of cardiomyocytes and regulate inflammation. Important actions of TGF-β superfamily members may be mediated through activation of Smad-dependent or non-Smad pathways. The critical role of TGF-β signaling cascades in cardiac repair, remodeling, fibrosis, and regeneration may suggest attractive therapeutic targets for myocardial infarction patients. However, the pleiotropic, cell-specific, and context-dependent actions of TGF-β superfamily members pose major challenges in therapeutic translation.
Highlights
Myocardial infarction is typically caused by thrombotic occlusion of a coronary artery, leading to prolonged cessation of blood flow in the territory subserved by the vessel
Inflammatory chemokines and cytokines are critically involved in the reparative process, mediating activation of macrophages that clear the wound from dead cells and matrix debris, and triggering expansion of reparative cells
TGF-β1, β2, and β3 are activated in the infarcted myocardium and may regulate phenotype and function of all cell types involved in cardiac injury and repair
Summary
Myocardial infarction is typically caused by thrombotic occlusion of a coronary artery, leading to prolonged cessation of blood flow in the territory subserved by the vessel. TGF-β1, β2, and β3 are activated in the infarcted myocardium and may regulate phenotype and function of all cell types involved in cardiac injury and repair. Effects of TGF-β on Ischemic Cardiomyocytes Early studies in isolated perfused hearts undergoing brief myocardial ischemia followed by reperfusion, suggested protective effects of TGF-β, mediated through attenuation of oxidative stress and reduced release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α [39].
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