Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012, China.
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012, China.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):729-34. doi: 10.1016/j.bbrc.2014.06.044. Epub 2014 Jun 17.
Increased pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Isorhynchophylline (IRN) is a tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether IRN can influence the development of PAH. Here we examined the effect of IRN on monocrotaline (MCT) induced PAH in rats. Our data demonstrated that IRN prevented MCT induced PAH in rats, as assessed by right ventricular (RV) pressure, the weight ratio of RV to (left ventricular+septum) and RV hypertrophy. IRN significantly attenuated the percentage of fully muscularized small arterioles, the medial wall thickness, and the expression of smooth muscle α-actin (α-SMA) and proliferating cell nuclear antigen (PCNA). In vitro studies, IRN concentration-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of PASMCs. Fluorescence-activated cell-sorting analysis showed that IRN caused G0/G1 phase cell cycle arrest. IRN-induced growth inhibition was associated with downregulation of Cyclin D1 and CDK6 as well as an increase in p27Kip1 levels in PDGF-BB-stimulated PASMCs. Moreover, IRN negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rβ, ERK1/2, Akt/GSK3β, and signal transducers and activators of transcription 3 (STAT3). These results demonstrate that IRN could inhibit PASMCs proliferation and attenuate pulmonary vascular remodeling after MCT induction. These beneficial effects were at least through the inhibition of PDGF-Rβ phosphorylation and its downstream signaling pathways. Therefore, IRN might be a potential candidate for the treatment of PAH.
肺动脉平滑肌细胞（PASMCs）增殖增加是肺动脉高压（PAH）肺血管重构的关键病理生理组成部分。异钩藤碱（IRN）是一种从中药钩藤中分离出来的四环吲哚生物碱。它长期以来一直被临床用于治疗心血管和脑血管疾病。然而，对于 IRN 是否会影响 PAH 的发展知之甚少。在这里，我们研究了 IRN 对野百合碱（MCT）诱导的大鼠 PAH 的影响。我们的数据表明，IRN 可预防 MCT 诱导的大鼠 PAH，评估指标包括右心室（RV）压力、RV 与（左心室+室间隔）的重量比和 RV 肥大。IRN 显著减弱了完全肌化小动脉的比例、中膜厚度以及平滑肌α-肌动蛋白（α-SMA）和增殖细胞核抗原（PCNA）的表达。在体外研究中，IRN 浓度依赖性地抑制血小板衍生生长因子（PDGF）-BB 诱导的 PASMCs 增殖。荧光激活细胞分选分析表明，IRN 导致 G0/G1 期细胞周期停滞。IRN 诱导的生长抑制与下调细胞周期蛋白 D1 和 CDK6 以及 PDGF-BB 刺激的 PASMCs 中 p27Kip1 水平升高有关。此外，IRN 负调控 PDGF-BB 诱导的 PDGF-Rβ、ERK1/2、Akt/GSK3β 和信号转导和转录激活因子 3（STAT3）的磷酸化。这些结果表明，IRN 可抑制 MCT 诱导后的 PASMCs 增殖并减轻肺血管重构。这些有益作用至少是通过抑制 PDGF-Rβ 磷酸化及其下游信号通路实现的。因此，IRN 可能是治疗 PAH 的潜在候选药物。
