Rapamycin reduced pulmonary vascular remodelling by inhibiting cell proliferation via Akt/mTOR signalling pathway down-regulation in the carotid artery-jugular vein shunt pulmonary hypertension rat model
Rapamycin reduced pulmonary vascular remodelling by inhibiting cell proliferation via Akt/mTOR signalling pathway down-regulation in the carotid artery-jugular vein shunt pulmonary hypertension rat model
复制标题
雷帕霉素通过下调 Akt/mTOR 信号通路抑制细胞增殖，减少颈动脉-颈静脉分流肺动脉高压大鼠模型中的肺血管重塑
DOI：
10.1093/icvts/ivx053
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发表时间：
2017
影响因子：
--
通讯作者：
Zhongkai Wu
中科院分区：
文献类型：
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作者：
Xiaofan Ma;Jianping Yao;Yuan Yue;Shangming Du;Han Qin;Jian Hou;Zhongkai Wu
目的肺动脉高压（PAH）是先天性心脏病的常见并发症。然而，对多环芳烃的有效治疗是罕见的。本研究旨在探讨雷帕霉素对颈动脉-颈静脉（CA-JV）分流PAH大鼠模型中PAH的抑制作用及其机制。方法将24只Sprague-Dawley大鼠随机分为对照组、CA-JV分流组和治疗组。治疗组给予雷帕霉素（2mg /kg/天），CA-JV分流组给予安慰剂。通过血流动力学评估、肺组织取样形态学分析、免疫荧光和western blot分析来评估雷帕霉素对PAH的影响。结果雷帕霉素可减轻CA-JV分流诱导的PAH模型大鼠肺血管过度循环引起的右心室收缩压（RVSP）升高、右心室肥厚（RVSP: CA-JV vs CA-JV +雷帕霉素，P= 0.017； RV: CA-JV vs CA-JV +雷帕霉素，P= 0.022）以及肺内血管增厚（厚度指数：CA-JV vs CA-JV +雷帕霉素，P= 0.028；面积指数：CA-JV vs CA-JV +雷帕霉素，P= 0.014）。雷帕霉素降低肺组织中指定细胞增殖标志物（α-平滑肌肌动蛋白）和雷帕霉素（mTOR）途径组分机制靶蛋白的表达水平（P -mTOR: CA-JV vs CA-JV +雷帕霉素，P= 0.004； P - raptor: CA-JV vs CA-JV +雷帕霉素，P= 0.000； P - s6k1: CA-JV vs CA-JV +雷帕霉素，P= 0.000； P - akt: CA-JV vs CA-JV +雷帕霉素，P= 0.001； P - rheb: CA-JV vs CA-JV +雷帕霉素，P= 0.000）。结论在CA-JV分流诱导的PAH模型中，斯帕霉素通过下调Akt/mTOR信号通路抑制细胞增殖，从而降低肺血管重构。因此，雷帕霉素可能是治疗多环芳烃的一种新的候选药物。
OBJECTIVESPulmonary arterial hypertension (PAH) is a common complication of congenital heart disease. However, effective treatments for PAH are rare. This study aimed to investigate the inhibitory effects of rapamycin on PAH in the carotid artery–jugular vein (CA-JV) shunt PAH rat model as well as the mechanism underlying these effects.METHODSTwenty-four Sprague–Dawley rats were randomized into the following 3 groups: a control group, a CA-JV shunt group and a treatment group. Rapamycin (2 mg/kg/day) was administered to the treatment group, and placebo was administered to the CA-JV shunt group. Haemodynamic evaluations, pulmonary tissue samplings for morphometry and immunofluorescence and western blot analyses were performed to evaluate the effects of rapamycin on PAH.RESULTSRapamycin attenuated the increase of right ventricular systolic pressure (RVSP) and the right ventricular (RV) hypertrophy (RVSP: CA-JV vs CA-JV + rapamycin,P= 0.017; RV: CA-JV vs CA-JV + rapamycin,P= 0.022), as well as the intrapulmonary vessel thickening (thickness index: CA-JV vs CA-JV + rapamycin,P= 0.028; area index: CA-JV vs CA-JV + rapamycin,P= 0.014), induced by overcirculation of the pulmonary vasculature in the CA-JV shunt-induced PAH rat model. Rapamycin decreased the expression level of the indicated cell proliferation marker (α-smooth muscle actin) in the lung vessel and mechanistic target of rapamycin (mTOR) pathway components (p-mTOR: CA-JV vs CA-JV + rapamycin,P= 0.004; p-Raptor: CA-JV vs CA-JV + rapamycin,P= 0.000; p-S6K1: CA-JV vs CA-JV + rapamycin,P= 0.000; p-Akt: CA-JV vs CA-JV + rapamycin,P= 0.001; p-Rheb: CA-JV vs CA-JV + rapamycin,P= 0.000) in pulmonary tissue.CONCLUSIONSRapamycin reduced pulmonary vascular remodelling by inhibiting cell proliferation via Akt/mTOR signalling pathway down-regulation in the CA-JV shunt-induced PAH model in rats. Thus, rapamycin may be a novel candidate drug for the treatment of PAH.