异钩藤碱对肺动脉高压有保护作用,抑制PASMCs增殖。

PubMed ID
G H
发表日期 2014年Jul月

原始出处 生物化学和生物物理学研究通讯
Biochemical and biophysical research communications
作者 Guo  Haipeng  Zhang  Xin  Cui  Yuqian  Deng  Wei  Xu  Dachun  Han  Hui  Wang  Hao  Chen  Yuguo  Li  Yu  Wu  Dawei 

文献标题 异钩藤碱对肺动脉高压有保护作用,抑制PASMCs增殖。
Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation.
Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation.

文献摘要

肺动脉平滑肌细胞(PASMCs)增殖增加是肺动脉高压(PAH)肺血管重构的重要病理生理学组成部分。异钩藤碱(isorhynchophyline,IRN)是从钩藤中提取的一种四环素类生物碱。临床上长期用于心脑血管疾病的治疗。然而,IRN是否能影响PAH的发展却鲜为人知。本文研究了IRN对野百合碱(MCT)诱导的大鼠PAH的影响。我们的数据表明,IRN可通过右心室(RV)压力、RV与(左心室+间隔)的重量比和RV肥大来预防MCT诱导的大鼠PAH。IRN能显著降低完全肌化小动脉的百分率、内侧壁厚度以及平滑肌α-actin(α-SMA)和增殖细胞核抗原(PCNA)的表达。体外研究表明,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。荧光活化细胞分选分析显示IRN引起G0/G1期细胞周期阻滞。IRN诱导的生长抑制与PDGF-BB刺激的PASMCs中cyclind1和CDK6的下调以及p27Kip1水平的升高有关。此外,IRN负调控PDGF-BB诱导的PDGF-Rβ、ERK1/2、Akt/GSK3β、信号转导子和转录激活子3(STAT3)的磷酸化。这些结果表明IRN能抑制MCT诱导后PASMCs增殖,减轻肺血管重构。这些有益的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的一个潜在候选药物。


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.

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.


获取全文 10.1016/j.bbrc.2014.06.044