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  • Title: Fluorofenidone inhibits transforming growth factor-beta1-induced cardiac myofibroblast differentiation.
    Author: Chen LX, Yang K, Sun M, Chen Q, Wang ZH, Hu GY, Tao LJ.
    Journal: Pharmazie; 2012 May; 67(5):452-6. PubMed ID: 22764581.
    Abstract:
    Cardiac myofibroblast differentiation, characterized by expression of alpha-smooth muscle actin (alpha-SMA) and fibrillar collagens, plays a key role in the adverse myocardial remodeling. Fluorofenidone (1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD) is a novel pyridone antifibrotic agent, which exerts a strong antifibrotic effect. This study investigated the potential role of AKF-PD in suppressing cardiac myofibroblast conversion induced by transforming growth factor-beta1 (TGF-beta1) and the related mitogen-activated protein kinase (MAPK) signaling pathways in neonatal rat cardiac fibroblasts. The MAPK inhibitors used for pathway determination are c-Jun NH(2)-terminal kinase (JNK) inhibitor II (JNK inhibitor), PD98059 (extracellular signal-regulated kinase inhibitor (ERK) inhibitor) and SB203580 (p38 MAPK inhibitor). Cell proliferation was evaluated by multiply-table tournament (MTT) assay. The expressions of fibronectin (FN), alpha-SMA, phosphorylated ERK1/2 (pERK1/2) and ERK1/2 were investigated using Western blot analysis. AKF-PD remarkablely reduced the proliferative response of cardiac fibroblasts by 27.57% compared with TGF-beta1 stimulated group. AKF-PD, PD98059, and JNK inhibitor II completely prevented TGF-beta1-induced FN protein production. In addition, AKF-PD, PD98059 and SB203580 greatly attenuated alpha-SMA expression induced by TGF-beta1. Furthermore, AKF-PD significantly blocked TGF-beta1-induced phosphorylation of ERK. These results indicate that (1) AKF-PD inhibits TGF-beta1-induced myofibroblast differentiation; (2) the anti-fibrotic effects of AKF-PD are partially mediated by ERK phosphorylation.
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