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<p>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.</p>

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Cardiomyocyte-derived TGFB3 attenuates cardiac fibrosis and preserves cardiac function in heart failure

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Jizhong Xuan,
  • Jiayu Zhou,
  • Yuanji Huang,
  • Mengyu Huang,
  • Shengyan Pu,
  • Liang Fang,
  • Yuxuan Chen,
  • Jieyuan Xue

摘要

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.