Cardiomyocyte-specific deletion of TGFB3 exacerbated cardiac dysfunction and fibrosis following pressure overload by enhancing SMAD3 phosphorylation and fibroblast activation.
Cardiomyocyte-derived TGFB3 acts as an endogenous protective factor against pathological cardiac fibrosis in heart failure by competitively inhibiting TGFB1-mediated Smad3 activation.
Heart failure, the common end-stage of cardiovascular diseases, features cardiac fibrosis. Transforming growth factor-β3 (TGFB3), a key TGFB/SMAD ligand, is upregulated in cardiac disorders, but its cellular source and precise role are debated. This study examined TGFB3 in human and mouse heart failure tissues. Histological and molecular analyses showed its increase mainly from cardiomyocytes, induced by angiotensin II. Circulating TGFB3 in patients positively correlated with plasma proBNP, a heart failure severity marker. A cardiomyocyte-specific TGFB3 knockout mouse model showed its absence worsens cardiac dysfunction and fibrosis under pressure overload. Mechanically, TGFB3 competes with TGFB1 for receptors, reducing Smad3 phosphorylation and profibrotic gene activation. Loss of TGFB3 in cardiomyocytes increased expression of profibrotic mediators such as CTGF and SERPINE1, ultimately accelerating fibrotic remodeling during HF progression. These findings identify cardiomyocyte-derived TGFB3 as a crucial endogenous modulator that protects against pathological cardiac fibrosis and highlight its therapeutic potential in HF.
Xuan et al. (Mon,) conducted a other in Heart failure (n=35). Cardiomyocyte-specific TGFB3 knockout vs. Wild-type/sham controls was evaluated on Cardiac function (ejection fraction, fractional shortening) and cardiac fibrosis. Cardiomyocyte-specific deletion of TGFB3 exacerbated cardiac dysfunction and fibrosis following pressure overload by enhancing SMAD3 phosphorylation and fibroblast activation.