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Wnt3a upregulation is involved in TGFβ1-induced cardiac hypertrophy
Cytokine ( IF 3.7 ) Pub Date : 2021-02-01 , DOI: 10.1016/j.cyto.2020.155376
Tao Li 1 , Xiaofei Weng 1 , Siya Cheng 2 , Dongxing Wang 2 , Guanchang Cheng 2 , Hai Gao 3 , Yanming Li 2
Affiliation  

Pathological cardiac hypertrophy, characterized by enlarged cell size and fetal gene reactivation, ultimately leads to cardiac dysfunction and heart failure. The expression of transforming growth factor beta 1 (TGFβ1) is often elevated in experimental models of cardiac hypertrophy. In the present study, we observed the activation of Wnt/β-catenin signaling in TGFβ1-induced cardiac hypertrophy. TGFβ1 stimulation decreased the phosphorylation levels of β-catenin and triggered the nuclear accumulation of β-catenin. In turn, TGFβ1 enhanced the expression of c-Myc, which is a transcriptional target of canonical Wnt/β-catenin pathway. Knockdown of β-catenin completely blocked TGFβ1-induced c-Myc upregulation. Wnt3a is an important Wnt ligand associated with cardiac fibrosis and hypertrophy. Further investigation revealed that TGFβ1 can upregulate Wnt3a expression in an ALK5-Smad2/3-dependent manner. A consensus Smad binding sequence is located within the Wnt3a promoter, and TGFβ1 stimulation enhanced recruitment of Smad2/3 onto the Wnt3a promoter. Meanwhile, Wnt3a overexpression also stimulated TGFβ1 expression. Chemical inhibition of Wnt/β-catenin signaling partially attenuated TGFβ1-induced hypertrophic responses. These findings suggest crosstalk between TGFβ1 and canonical Wnt/β-catenin pathways in cardiac hypertrophy.

中文翻译:

Wnt3a 上调参与 TGFβ1 诱导的心脏肥大

以增大的细胞大小和胎儿基因重新激活为特征的病理性心脏肥大最终导致心功能不全和心力衰竭。在心脏肥大的实验模型中,转化生长因子 β 1 (TGFβ1) 的表达经常升高。在本研究中,我们观察到 TGFβ1 诱导的心脏肥大中 Wnt/β-catenin 信号传导的激活。TGFβ1刺激降低了β-连环蛋白的磷酸化水平并引发了β-连环蛋白的核积累。反过来,TGFβ1 增强了 c-Myc 的表达,c-Myc 是经典 Wnt/β-catenin 通路的转录靶标。β-连环蛋白的敲低完全阻断了 TGFβ1 诱导的 c-Myc 上调。Wnt3a 是与心脏纤维化和肥大相关的重要 Wnt 配体。进一步的研究表明,TGFβ1 可以以 ALK5-Smad2/3 依赖的方式上调 Wnt3a 的表达。共有的 Smad 结合序列位于 Wnt3a 启动子内,并且 TGFβ1 刺激增强了 Smad2/3 向 Wnt3a 启动子的募集。同时,Wnt3a 过表达也刺激了 TGFβ1 的表达。Wnt/β-连环蛋白信号的化学抑制部分减弱了 TGFβ1 诱导的肥大反应。这些发现表明 TGFβ1 和经典 Wnt/β-catenin 通路在心脏肥大中的串扰。Wnt/β-连环蛋白信号的化学抑制部分减弱了 TGFβ1 诱导的肥大反应。这些发现表明 TGFβ1 和经典 Wnt/β-catenin 通路在心脏肥大中的串扰。Wnt/β-连环蛋白信号的化学抑制部分减弱了 TGFβ1 诱导的肥大反应。这些发现表明 TGFβ1 和经典 Wnt/β-catenin 通路在心脏肥大中的串扰。
更新日期:2021-02-01
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