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- Title
Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertension of rats.
- Authors
Li, Xian-Wei; Du, Jie; Hu, Gao-Yun; Hu, Chang-Ping; Li, Dai; Li, Yuan-Jian; Li, Xiao-Hui
- 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.
- Subjects
TRANSFORMING growth factors; PYRIDONE derivatives; CELLULAR signal transduction; PULMONARY hypertension; HYPOXEMIA; CARDIOVASCULAR system; TISSUE remodeling; LABORATORY rats
- Publication
Canadian Journal of Physiology & Pharmacology, 2014, Vol 92, Issue 1, p58
- ISSN
0008-4212
- Publication type
Article
- DOI
10.1139/cjpp-2013-0056