LAUSR

Transforming growth factor‐β (TGF‐β) signaling pathway is involved in fibrosis in most, if not all forms of cardiac diseases. Here, we evaluate a positive feedback signaling the loop of TGF‐β1/promyelocytic leukemia (PML) SUMOylation/Pin1 promoting the cardiac fibrosis. To test this hypothesis, the mice underwent transverse aortic constriction (3 weeks) were developed and the morphological evidence showed obvious interstitial fibrosis with TGF‐β1, Pin1 upregulation, and increase in PML SUMOylation. In neonatal mouse cardiac fibroblasts (NMCFs), we found that exogenous TGF‐β1 induced the upregulation of TGF‐β1 itself in a time‐ and dose‐dependent manner, and also triggered the PML SUMOylation and the formation of PML nuclear bodies (PML‐NBs), and consequently recruited Pin1 into nuclear to colocalize with PML. Pharmacological inhibition of TGF‐β signal or Pin1 with LY364947 (3 μM) or Juglone (3 μM), the TGF‐β1‐induced PML SUMOylation was reduced significantly with downregulation of the messenger RNA and protein for TGF‐β1 and Pin1. To verify the cellular function of PML by means of gain‐ or loss‐of‐function, the positive feedback signaling loop was enhanced or declined, meanwhile, TGF‐β‐Smad signaling pathway was activated or weakened, respectively. In summary, we uncovered a novel reciprocal loop of TGF‐β1/PML SUMOylation/Pin1 leading to myocardial fibrosis.