title: Fluorofenidone inhibits transforming growth factor-beta1-induced cardiac myofibroblast differentiation.
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.
authors: Division of Cardiology, Department of Internal Medicine, The Third Xiangya Hospital, Changsha, Hunan, China.
authors: Ling-Xi
authors: LX
authors: Chen
authors: Kan
authors: K
authors: Yang
authors: Ming
authors: M
authors: Sun
authors: Qiong
authors: Q
authors: Chen
authors: Zhao-He
authors: ZH
authors: Wang
authors: Gao-Yun
authors: GY
authors: Hu
authors: Li-Jian
authors: LJ
authors: Tao
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis; D005355:Fibrosis; D005419:Flavonoids / Q000494:pharmacology; D007202:Indicators and Reagents; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D058628:Myofibroblasts / Q000187:drug effects*; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D000199:Actins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D005419:Flavonoids; D007202:Indicators and Reagents; D011728:Pyridones; D053773:Transforming Growth Factor beta1; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one