Wnt3a upregulation is involved in TGFβ1-induced cardiac hypertrophy.

Abstract 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.