- Authors: Gu, J., Liu, X., Wang, Q. X., Tan, H. W., Guo, M., Jiang, W. F., Zhou, L.
- Year: 2012
- Journal: Exp Cell Res 318 2105-15
- Applications: in vitro / siRNA / INTERFERin
- Cell type: Mouse atrial cardiac fibroblasts
Description: Normal human dermal fibroblasts
The activation of transforming growth factor-beta1(TGF-beta1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGFbeta1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGFbeta-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-beta1/non-Smad signaling pathways. In the present study, we explored the role of TGF-beta1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 muM) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 muM) also promoted TGFbeta1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGFbeta1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGFbeta1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis.