Zhang Yongtao, Cui Yuqian, Deng Wei, Wang Hao, Qin Weidong, Huang Chengmin, Li Chen, Zhang Jianning, Guo Yuan, Wu Dawei, Guo Haipeng
Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.
Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
Clin Exp Pharmacol Physiol. 2017 Mar;44(3):362-370. doi: 10.1111/1440-1681.12705.
Pulmonary vascular remodelling is a common feature among the heterogeneous disorders that cause pulmonary arterial hypertension (PAH), and pulmonary arterial smooth muscle cells (PASMCs) proliferation impact the long-term prognosis of the patient. Isoquercitrin (IQC) is a flavonoid with anti-oxidative, anti-inflammatory and anti-proliferative activations. This study aimed to investigate whether IQC could prevent PASMCs proliferation and vascular remodelling in monocrotaline (MCT) induced PAH. Male Wistar rats were administered with Vehicle or 0.1% IQC maintain feed after MCT (40 mg/kg) injection. Haemodynamic changes, right ventricular hypertrophy and lung morphological features were assessed 3 weeks later. MCT-induced PAH, pulmonary vascular remodelling and PASMCs proliferation in Vehicle-treated rats. IQC reduced the right ventricle systolic pressure (RVSP), the ratio of RV/LV+S and the RV hypertrophy. IQC significantly alleviated the expression of proliferating cell nuclear antigen (PCNA), smooth muscle α-actin (α-SMA), and the percentage of fully muscularized small arterioles. In vitro studies, PASMCs were pretreated with IQC and stimulated with platelet-derived growth factor (PDGF)-BB (20 ng/mL). IQC suppressed PDGF-BB-induced PASMCs proliferation and caused G0/G1 phase cell cycle arrest. IQC downregulated the expression of Cyclin D1 and CDK4 as well as inhibited p27Kip1 degradation. Meanwhile, IQC negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rβ, Akt/GSK3β and ERK1/2. IQC ameliorated MCT-induced pulmonary vascular remodelling via suppressing PASMCs proliferation and blocking PDGF-Rβ signalling pathway.
肺血管重塑是导致肺动脉高压（PAH）的异质性疾病的共同特征，肺动脉平滑肌细胞（PASMCs）增殖影响患者的长期预后。异槲皮苷（IQC）是一种具有抗氧化、抗炎和抗增殖活性的黄酮类化合物。本研究旨在探讨IQC是否能预防野百合碱（MCT）诱导的PAH中PASMCs增殖和血管重塑。雄性Wistar大鼠在注射MCT（40mg/kg）后给予溶剂或0.1%IQC维持饲料。3周后评估血流动力学变化、右心室肥厚和肺形态特征。MCT诱导了溶剂处理大鼠的PAH、肺血管重塑和PASMCs增殖。IQC降低了右心室收缩压（RVSP）、RV/LV+S比值和右心室肥厚。IQC显著减轻了增殖细胞核抗原（PCNA）、平滑肌α-肌动蛋白（α-SMA）的表达以及完全肌化小动脉的百分比。在体外研究中，PASMCs用IQC预处理并用血小板衍生生长因子（PDGF）-BB（20ng/mL）刺激。IQC抑制PDGF-BB诱导的PASMCs增殖并导致G0/G1期细胞周期停滞。IQC下调细胞周期蛋白D1和细胞周期蛋白依赖性激酶4（CDK4）的表达并抑制p27Kip1降解。同时，IQC负向调节PDGF-BB诱导的PDGF-Rβ、Akt/糖原合成酶激酶3β（GSK3β）和细胞外信号调节激酶1/2（ERK1/2）的磷酸化。IQC通过抑制PASMCs增殖和阻断PDGF-Rβ信号通路改善MCT诱导的肺血管重塑。
