Key result
TSC-22 promotes TGF-β-mediated cardiac myofibroblast differentiation and myocardial fibrosis by antagonizing Smad7 activity.
Why the study?
The regulation of TGF-β signaling duration and intensity in cardiac fibrosis and the role of TSC-22 in this process were not fully understood.
TSC-22 regulates TGF-β signaling via a positive-feedback mechanism and contributes to myocardial fibrosis, highlighting a potential molecular target for anti-fibrotic therapies.
May support TSC-22 inhibition as anti-fibrotic strategy; animal data leave open human translation and clinical validation.
Transforming growth factor β (TGF-β) plays a critical role in tissue fibrosis. The duration and intensity of TGF-β signaling are tightly regulated. Here we report that TSC-22 (TGF-β-stimulated clone 22) facilitates TGF-β signaling by antagonizing Smad7 activity to increase receptor stability. TSC-22 enhances TGF-β-induced Smad2/3 phosphorylation and transcriptional responsiveness. The stimulatory effect of TSC-22 is dependent on Smad7, as silencing Smad7 expression abolishes it. TSC-22 interacts with TGF-β type I receptor TβRI and Smad7 in mutually exclusive ways and disrupts the association of Smad7/Smurfs with TβRI, thereby preventing ubiquitination and degradation of the receptor. We also found that TSC-22 can promote the differentiation of cardiac myofibroblasts by increasing expression of the fibrotic genes for α-smooth muscle actin (α-SMA), PAI-1, fibronectin, and collagen I, which is consistent with upregulation of TSC-22, phospho-Smad2/3, and the fibrotic genes in isoproterenol-induced rat myocardial fibrotic hearts. Taken together with the notion that TGF-β induces TSC-22 expression, our findings suggest that TSC-22 regulates TGF-β signaling via a positive-feedback mechanism and may contribute to myocardial fibrosis.
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Yan et al. (2011) studied Myocardial fibrosis. TSC-22 was evaluated on Cardiac myofibroblast differentiation and TGF-β signaling regulation. TSC-22 promotes TGF-β-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity and increasing receptor stability, contributing to myocardial fibrosis.
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