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 contextdependence 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.

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

“…Despite the critical involvement of TGF‐β signalling in cardiac injury and repair (Frangogiannis, ), targeting TGF‐β following MI poses several major challenges. First, TGF‐βs are known to modulate phenotype and function of all cell types involved in cardiac injury and repair.…”

Length doesn't matter—telomere damage triggers cellular senescence in the ageing heart

“…While initially both telomeric DNA and non-telomeric DNA were found to be damaged, only telomeric DNA damage persisted and triggered TAF formation. Other investigators previously have shown that both GDF15 and TGFb2 are induced in the infarcted heart (Frangogiannis, 2017), suggesting that production of these cytokines is not unique to the senescent heart. DNA damage was also induced by a TRF1-FokI fusion protein (Dilley et al, 2016), which Developmental Dynamics, National Heart and Lung Institute (NHLI), Imperial College London, London, UK.…”

“…Unfortunately, the authors did not characterise the effects of conditioned medium or of Edn3 and TGFb2 on adult cardiac myocytes. Other investigators previously have shown that both GDF15 and TGFb2 are induced in the infarcted heart (Frangogiannis, 2017), suggesting that production of these cytokines is not unique to the senescent heart.…”

iTRAQ‐Based Proteomic Analysis Exploring the Influence of Hypoxia on the Proteome of Dental Pulp Stem Cells under 3D Culture

“…TGF‐β1 was considered as a vital cytokine that regulates a broad diversity of physiological and pathological processes, including tissue wound healing, inflammation, cell proliferation, differentiation, migration, and extracellualr matrix (ECM) synthesis. A series of studies demonstrated that TGF‐β signaling pathways play an important role in regulation of the cellular events associated with tissue regeneration and repair, by modulating injurious, inflammatory, reparative, angiogenic, and fibrogenic responses . In regenerative endodontics, TGF‐β1 involves in pro‐survival, pro‐angiogenesis, proliferation, and anti‐apoptosis of dental pulp stem cells.…”