Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertension of rats
Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertension of rats
复制标题
氟非尼酮减弱缺氧诱导的大鼠肺动脉高压的血管重塑。
DOI：
10.1139/cjpp-2013-0056
复制
发表时间：
2014-01-01
影响因子：
2.1
通讯作者：
Li, Xiao-Hui
中科院分区：
文献类型：
--
作者：
Li, Xian-Wei;Du, Jie;Li, Xiao-Hui
氟非尼酮（AKF-PD）是一种新型的吡啶酮衍生物，靶向转化生长因子-β（1）（TGF-β（1））信号传导。以往的研究已经证明，AKF-PD作为抗纤维化剂在肺纤维化和肾纤维化模型中发挥作用。活化的TGF-β（1）信号被认为是肺动脉高压（PH）的主要特征。TGF-β（1）对肺动脉平滑肌细胞（PASMCs）发挥强大的促增殖作用，因此促进血管重塑。本研究旨在探讨AKF-PD对缺氧性肺动脉高压大鼠血管重构的影响。通过ELISA、免疫组织化学、实时PCR或Western印迹分析TGF-β（1）、胶原I和胶原III的表达。用BrdU掺入法和流式细胞术检测PASMCs的增殖情况。结果表明，AKF-PD处理（0.5或1.0 g. (kg d（-1））治疗4周可减轻肺血管重构并改善血流动力学参数。在体内和体外，AKF-PD均显著下调TGF-β 1水平。此外，AKF-PD可显著抑制缺氧和TGF-β 1诱导的PASMC增殖和胶原表达。这些结果表明，AKF-PD通过调节TGF-β（1）表达、PASMC增殖和细胞外基质来改善大鼠缺氧诱导的PH进展。
Fluorofenidone (AKF-PD) is a novel pyridone derivate that targets transforming growth factor-beta(1) (TGF-beta(1)) signaling. Previous studies have proven that AKF-PD functions as an antifibrotic agent in pulmonary fibrosis and renal fibrosis models. Activated TGF-beta(1) signaling is thought to be a major feature of pulmonary hypertension (PH). TGF-beta(1) 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-beta(1), 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-beta(1) level was significantly down-regulated by AKF-PD both in vivo and in vitro. Furthermore, hypoxia-and TGF-beta(1)-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-beta(1) expression, PASMC proliferation, and the extracellular matrix.