title: Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertension of rats.
abstract: Fluorofenidone (AKF-PD) is a novel pyridone derivate that targets transforming growth factor-β1 (TGF-β1) signaling. Previous studies have proven that AKF-PD functions as an antifibrotic agent in pulmonary fibrosis and renal fibrosis models. Activated TGF-β1 signaling is thought to be a major feature of pulmonary hypertension (PH). TGF-β1 exerts powerful pro-proliferation effects on pulmonary arterial smooth muscle cells (PASMCs), and hence, prompts vascular remodeling. This study is designed to investigate the effect of AKF-PD on vascular remodeling in a rat model of hypoxia-induced PH. PH was induced in rats by 4 weeks of hypoxia. The expression of TGF-β1, collagen I, and collagen III was analyzed by ELISA, immunohistochemistry, real-time PCR, or Western blot. Proliferation of cultured PASMCs was determined by the BrdU incorporation method and flow cytometry. The results showed that AKF-PD treatment (0.5 or 1.0 g·(kg body mass)·d(-1)) for 4 weeks attenuated pulmonary vascular remodeling and improved homodynamic parameters. TGF-β1 level was significantly down-regulated by AKF-PD both in vivo and in vitro. Furthermore, hypoxia- and TGF-β1-induced PASMC proliferation and collagen expression were both significantly suppressed by AKF-PD. These results suggest that AKF-PD ameliorates the progression of PH induced by hypoxia in rats through its regulation of TGF-β1 expression, PASMC proliferation, and the extracellular matrix.
authors.affiliation: a Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road No. 110, Changsha 410078, China.
authors.forename: Xian-Wei
authors.initials: XW
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Gao-Yun
authors.initials: GY
authors.lastname: Hu
authors.forename: Chang-Ping
authors.initials: CP
authors.lastname: Hu
authors.forename: Dai
authors.initials: D
authors.lastname: Li
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Li
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011728:Pyridones / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D024042:Collagen Type I; D024043:Collagen Type II; D011728:Pyridones; D053773:Transforming Growth Factor beta1