大麻素受体1在缺氧性肺动脉高压中调控肺动脉内皮间充质转化的作用及机制

Pulmonary artery hypertension (PAH) is a malignant progressive disease, whose pathological process includes pulmonary vascular contraction and remodeling. Hypoxia-induced endothelial mesenchymal transition (EndMT) is a key factor in pulmonary artery remodeling, but the molecular mechanism of EndMT is unclear. We found that hypoxia up-regulated cannobinoid receptor 1(CB1) expression in pulmonary artery endothelium. Moreover, blocking CB1 inhibited not only the hypoxia-induced EndMT but also the activation of ATF-6, which was one signaling pathway of endoplasmic reticulum stress. Additionally, ATF-6 regulated the hypoxia-induced EndMT in pulmonary artery endothelial cells. Thus, we believe that hypoxia-up-regulated CB1 promotes pulmonary artery EndMT by activating endoplasmic reticulum stress. It will be proved by three studies, which are (1) clarifying the effect of CB1 on hypoxic pulmonary artery EndMT; (2) revealing the role of endoplasmic reticulum stress in CB1-regulated EndMT, and clarifying the molecular mechanism in CB1-regulated EndMT; (3) studying on the treatment of hypoxic PAH based on the key molecule and potential intervention target found in the molecular mechanism that CB1 regulates EndMT. This application will first explore the role of CB1 in hypoxic pulmonary artery EndMT. Moreover, revealing the molecular mechanism of EndMT regulated by CB1 will provide new drug targets and ideas for the PAH prevention and treatment.

肺动脉高压(PAH)是一种恶性进行性疾病，病理过程包括肺血管收缩和重构，缺氧诱导内皮间充质转化(EndMT)是血管重构的关键因素，分子机制尚不明确。我们发现缺氧上调肺动脉内皮中大麻素受体1(CB1)表达，阻断CB1可抑制缺氧诱导的EndMT并抑制内质网应激ATF-6通路激活；在细胞水平，ATF-6介导了缺氧诱导的EndMT。因而，我们认为缺氧上调的CB1通过激活内质网应激促进肺动脉EndMT。拟通过下述研究证明该假设：(1)阐明CB1对缺氧性肺血管EndMT的作用；(2)揭示内质网应激在CB1调控EndMT中的作用，阐明CB1调控EndMT的分子机制；(3)基于CB1调控EndMT分子机制的关键分子和潜在干预靶点治疗缺氧所致PAH的探索。本申请将首次探索CB1在缺氧性肺血管EndMT中的作用；揭示CB1调控EndMT的分子机制为肺动脉高压预防和治疗提供新的药物靶点和思路。

肺动脉高压(PAH)是一种恶性进行性疾病，病理过程包括肺血管收缩和重构，缺氧诱导内皮间充质转化(EndMT)是血管重构的关键因素，分子机制尚不明确。我们发现缺氧上调肺动脉内皮中大麻素受体1(CNR1)表达，阻断CNR1可抑制缺氧诱导的EndMT并抑制内质网应激ATF-6通路激活；缺氧通过转录因子HIF-1α结合CNR1启动子区，促进CNR1转录增加；CNR1通过激活内质网应激信号通路ATF-6，ATF-6通过转录因子EHF结合CDH5启动子区抑制CDH5的表达，从而促进肺动脉内皮EndMT。因而，缺氧通过HIF-1α上调的CNR1的表达，CNR1激活内质网应激关键蛋白ATF-6，进而促进转录因子EHF与CDH5启动子区结合抑制CDH5的表达诱导肺动脉EndMT。本研究首次探索CNR1在缺氧性肺血管EndMT中的作用，揭示CNR1调控EndMT的分子机制为肺动脉高压预防和治疗提供新的药物靶点和思路。