College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
Biomed Pharmacother. 2021 Jan;133:111056. doi: 10.1016/j.biopha.2020.111056. Epub 2020 Nov 28.
Pulmonary arterial hypertension (PAH) is a progressive and lethal cardiopulmonary. Pulmonary vascular remodeling (PVR) caused by excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) is the chief pathological feature of PAH. Dioscin is a natural product that possesses multiple pharmacological activities, but its effect on PAH remains unclear. In this study, effect of dioscin on vascular remodeling in PAH was assessed in hypoxia-induced PASMCs, hypoxia-induced and monocrotaline (MCT)-induced rats. Western blot, Real-time PCR and siRNA transfection tests were applied to evaluate the possible mechanisms of dioscin. In vitro experiments, results showed dioscin markedly inhibited the proliferation and migration, and promoted apoptosis of hypoxic PASMCs. In vivo, dioscin significantly decreased the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI), and improved pulmonary vascular stenosis in rats induced by hypoxia or MCT. Molecular mechanism studies showed that dioscin significantly reduced the expression of growth factor receptor-bound protein 2 (GRB2). Subsequently, dioscin reduced the expressions of Ras, Cyclin D1, CDK4, c-Fos, PCNA and p-ERK to inhibit proliferation and migration of PASMCs, inhibited p-PI3K and p-AKT levels and increased Bax/Bcl2 ratio to promote cell apoptosis. GRB2 siRNA transfection in PASMCs further confirmed that the inhibitory action of dioscin in PAH was evoked by adjusting GRB2/ERK/PI3K-AKT signal. Taken together, our study indicated that dioscin attenuates PAH through adjusting GRB2/ERK/PI3K-AKT signal to inhibit PASMCs proliferation and migration, and promote apoptosis, and dioscin may be developed as a therapeutic strategy for treating PAH in the future.
肺动脉高压（PAH）是一种进行性和致命的心肺疾病。肺血管重构（PVR）是由肺动脉平滑肌细胞（PASMCs）过度增殖和抗凋亡引起的，是 PAH 的主要病理特征。薯蓣皂苷元是一种具有多种药理活性的天然产物，但它对 PAH 的作用尚不清楚。在这项研究中，评估了薯蓣皂苷元对缺氧诱导的 PASMCs、缺氧诱导和野百合碱（MCT）诱导的大鼠血管重构的影响。采用 Western blot、Real-time PCR 和 siRNA 转染试验来评估薯蓣皂苷元的可能作用机制。在体外实验中，结果表明薯蓣皂苷元显著抑制了缺氧 PASMCs 的增殖和迁移，并促进了其凋亡。在体内，薯蓣皂苷元显著降低了由缺氧或 MCT 诱导的大鼠右心室收缩压（RVSP）和右心室肥厚指数（RVHI），并改善了肺动脉狭窄。分子机制研究表明，薯蓣皂苷元显著降低了生长因子受体结合蛋白 2（GRB2）的表达。随后，薯蓣皂苷元降低了 Ras、Cyclin D1、CDK4、c-Fos、PCNA 和 p-ERK 的表达，以抑制 PASMCs 的增殖和迁移，抑制了 p-PI3K 和 p-AKT 水平，并增加了 Bax/Bcl2 比值，以促进细胞凋亡。在 PASMCs 中转染 GRB2 siRNA 进一步证实，薯蓣皂苷元在 PAH 中的抑制作用是通过调节 GRB2/ERK/PI3K-AKT 信号来诱发的。总之，我们的研究表明，薯蓣皂苷元通过调节 GRB2/ERK/PI3K-AKT 信号来抑制 PASMCs 的增殖和迁移，促进凋亡，从而减轻 PAH，薯蓣皂苷元可能成为未来治疗 PAH 的一种治疗策略。
