针脚1
相扑蛋白
脯氨酸异构酶
癌症研究
转化生长因子
肽基脯氨酰异构酶
细胞生物学
纤维化
生物
循环(图论)
心脏纤维化
化学
遗传学
内科学
酶
医学
泛素
生物化学
数学
异构酶
基因
组合数学
作者
Di Wu,Di Huang,Liangliang Li,Ping Ni,Xiuxian Li,Bing Wang,Yanna Han,Xiaoqi Shao,Daqing Zhao,Wenfeng Chu,Bai‐Yan Li
摘要
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.
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