基于NF-κB-BMP信号通路探讨黄芩苷对肺动脉高压血管重构的作用及机制研究

项目名称： 基于NF-κB-BMP信号通路探讨黄芩苷对肺动脉高压血管重构的作用及机制研究

项目编号： No.81500042

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 栾云

作者单位： 山东大学

项目金额： 18万元

中文摘要： 肺动脉高压(PAH)是一种进行性恶化疾病，WHO功能分级为Ⅳ的PAH患者，预后较差。肺小动脉内膜增厚，血管阻力增加导致的右心室衰竭是主要病理改变。近几年血管重构越来越引起重视，但其确切机制尚不完全清楚。我们前期研究证实抑制NF-κB信号通路能逆转PAH造成的肺血管重构，黄芩苷通过下调NF-κB信号通路，能抑制血管重构对PAH产生保护作用。最新研究发现BMP与NF-κB信号通路共同参与了PAH血管重构的发生过程，可能存在互作位点，但具体机制研究较少。结合我们前期工作基础与国内外研究现状，本研究拟应用蛋白酶体抑制剂阻断NF-κB信号通路，利用siRNA技术沉默NF-κB p65和BMPR2基因，从不同角度对NF-κB-BMP信号通路中起调控作用的细胞因子、蛋白、基因进行评价，筛选作用位点。并基于NF-κB-BMP信号通路探讨黄芩苷抑制PAH血管重构的作用机制，为中药治疗PAH提供有益的探索。

中文关键词： 肺动脉高压；血管重构；NF-κB-BMP信号通路；黄芩苷；细胞凋亡

英文摘要： Pulmonary arterial hypertension (PAH) is characterized by functional and structural changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance, right ventricular dysfunction, lung vascular remodeling and loss of the distal pulmonary vasculature. There are large numbe of herapies have been proven useful in decreasing pulmonary arterial pressure, improving exercise tolerance and quality of life, but an effective therapy of the long-term outcome in this disorder is lacking. In recent years, studies have shown that endothelial dysfunction is an indispensable feature and an early event in the pathogenesis of PAH. Vascular remodeling is the common response in various classes of PAH and proliferation of pulmonary arterial smooth muscle cells (PASMCs) contributes to vascular remodeling mostly. Presistent high pulmonary arterial pressure leads to increased vascular resistence, right ventricle hypertrophy, heart failure and even death.There is growing interest in identifying the signal mechanism underlying the development of vascular remodeling and the transition to heart failure. Nuclear factor-κB (NF-κB) is a key transcription regulator in various cardiac disorders but the role of NF-κB remains limited in PAH-induced vascular remodeling and RVH. Bone morphogenetic protein (BMP) signaling plays a critical role in PAH. Dysfunction of BMP signaling has been thought as an important reason of PAH. Studies have shown that in animal models of PAH, BMP signaling pathway and NF-κB signaling pathways has important connection and involved in vascular remodeling process. The regulating of NF-κB-BMP signaling pathway in the lungs providing new mechanistic information about MCT-induced PAH and RVH. In our previous studies showed that baicalin can decrease the pulmonary artery pressure, reduce right ventricular hypertrophy, and attenuate pulmonary vascular remodeling. The mechanism may be through inhibiting the inflammatory reaction and regulation NF-κB-BMP signaling pathway, but the underlying mechanism remains elusive. Based on our previous work, this research intends to through blocking signal pathways and siRNA technology to study the regulating mechanism of NF-κB-BMP signaling pathway in the development of PAH induced vascular remodeling. On the other hand, the aim was to explore the protective effects of baicalin on PAH through regulating NF-κB-BMP signal pathway, these would provide beneficial exploration for Chinese medicine in the treatment of PAH.

英文关键词： Pulmonary arterial hypertension;Vascular remodeling;NF-κB-BMP signaling pathway;Baicalin;Cell apoptosis