Department of Geriatrics, Peking University First Hospital, Beijing 100034, P.R. China.
Int J Mol Med. 2018 May;41(5):2461-2472. doi: 10.3892/ijmm.2018.3462. Epub 2018 Feb 6.
The present study was designed to examine whether hypoxia induces the proliferation, migration and differentiation of pulmonary arterial fibroblasts (PAFs) via the PI3K/Akt/p70S6K signaling pathway. PAFs were subjected to normoxia (21% O2) or hypoxia (1% O2). The proliferation, migration, differentiation and cellular p110α, p‑Akt, and p‑p70S6K expression levels of the PAFs were examined in vitro. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and right ventricular weight/body weight ratio (RV/BW) were examined. The expression levels of p110α, p‑Akt, p70S6K, fibronectin and α‑SMA in the rat pulmonary vessels were also examined. Hypoxia significantly elevated the proliferation, migration and differentiation of rat PAFs. It also strongly elevated the expression of p110α, p‑Akt and p‑p70S6K in PAFs in vitro. NVP‑BEZ235 was revealed to significantly reduce the hypoxia‑induced proliferation, migration and differentiation. In vivo experiments demonstrated that hypoxia significantly induced the elevation of RVSP, RVHI, RV/BW, medial thickening, adventitious thickening, and fibronectin and collagen deposition around pulmonary artery walls. The expression of p110α, p‑Akt and p70S6K was evident in the pulmonary arteries of the hypoxic rats. NVP‑BEZ235 significantly reduced the hypoxia‑induced hypoxic pulmonary vascular remodeling, as well as fibronectin and collagen deposition in the pulmonary arteries. Therefore, hypoxia was demonstrated to induce the proliferation, migration and differentiation of PAFs and the hypoxic pulmonary vascular remodeling of rats via the PI3K/Akt/p70S6K signaling pathway.
本研究旨在探讨缺氧是否通过 PI3K/Akt/p70S6K 信号通路诱导肺动脉成纤维细胞（PAFs）的增殖、迁移和分化。将 PAFs 置于常氧（21% O2）或缺氧（1% O2）条件下。在体外检测 PAFs 的增殖、迁移、分化以及细胞内 p110α、p-Akt 和 p-p70S6K 的表达水平。此外，将大鼠维持在缺氧条件下，检测右心室收缩压（RVSP）、右心室肥厚指数（RVHI）和右心室重量/体重比（RV/BW）。还检测了大鼠肺血管中 p110α、p-Akt、p70S6K、纤连蛋白和α-SMA 的表达水平。缺氧显著增加了大鼠 PAFs 的增殖、迁移和分化。它还强烈增加了 PAFs 中 p110α、p-Akt 和 p-p70S6K 的表达。NVP-BEZ235 被证实可显著减少缺氧诱导的增殖、迁移和分化。体内实验表明，缺氧显著诱导 RVSP、RVHI、RV/BW、中膜增厚、外膜增厚以及肺动脉壁周围的纤连蛋白和胶原沉积增加。缺氧大鼠的肺血管中 p110α、p-Akt 和 p70S6K 的表达明显。NVP-BEZ235 显著减少了缺氧诱导的缺氧性肺血管重构以及肺血管中的纤连蛋白和胶原沉积。因此，缺氧通过 PI3K/Akt/p70S6K 信号通路诱导 PAFs 的增殖、迁移和分化以及大鼠的缺氧性肺血管重构。
