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.
Key points
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Ischaemic, mechanical, inflammatory and metabolic injuries induce the synthesis and activation of myocardial transforming growth factor-β (TGFβ) isoforms; generation of bioactive TGFβ requires release of proteases, deposition of matricellular proteins and activation of integrins.
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In the injured and remodelling myocardium, TGFβs regulate the phenotype and function of cardiomyocytes, fibroblasts, immune cells and vascular cells through activation of SMAD-dependent and SMAD-independent pathways.
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In cardiac pressure overload, activation of TGFβ signalling might preserve the extracellular matrix, preventing the generation of pro-inflammatory matrix fragments.
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In the healing phase after myocardial infarction, TGFβ regulates repair, suppressing macrophage-driven inflammation and stimulating fibroblast activation; however, prolonged or excessive TGFβ signalling promotes fibrosis and contributes to dysfunction in both myocardial infarction and cardiac pressure overload.
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TGFβs are involved in the pathogenesis of diabetic cardiomyopathy and in cardiac ageing, and fibrogenic TGFβ actions can stimulate atrial fibrosis, triggering atrial fibrillation, and contribute to genetic cardiomyopathy and inflammatory cardiomyopathy.
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Targeting TGFβ cascades in failing and remodelling hearts holds therapeutic promise but also poses major challenges related to the pleiotropic actions of TGFβ and the pathophysiological heterogeneity of cardiac diseases.
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Acknowledgements
N.G.F.’s laboratory is supported by NIH grants R01 HL76246, R01 HL85440 and R01 HL149407 and by US Department of Defense grant PR181464.
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Frangogiannis, N.G. Transforming growth factor-β in myocardial disease. Nat Rev Cardiol 19, 435–455 (2022). https://doi.org/10.1038/s41569-021-00646-w
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DOI: https://doi.org/10.1038/s41569-021-00646-w
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