Wnt3a upregulation is involved in TGFβ1-induced cardiac hypertrophy.

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.