充血型肺动脉高压中肺血管平滑肌增殖新机制-GPR91研究

Congestive pulmonary arterial hypertension（cPAH）remains a major complication of congenital heart disease（CHD） characterized by increasing proliferation of vascular smooth muscle cells. The fundamental paphological changes,such as PI3K/AKT activation, usually result in vascular remodeling and plexus and eventually lead to right heart failure, or even death. Our preliminary study suggested that the activation of GPR91 in rat pulmonary hypertension model. We hypothesis that GPR91 play an important role during the pulmonary hypertension pathological processes caused by PI3K/AKT activation. Therefore, our project will continue observe: i) GPR91 receptor expression, function regulation, signaling transduction in rat pulmonary hypertension model; ii) GPR91gene expression and histoimmunochemical analysis in myocardial biopsy in cPAH model and smooth muscle cells; iii) cellular proliferation, migration and angiogenic factor expression induced by GPR91 in pulmonary artery smooth muscle cells and vascular endothelial cells; iv) the functional regulation of GPR91 by gene expression, signaling inhibition, gene knock down on above experiments in vivo and in vitro. This study aim to test GPR91 receptor as the main role to cause cPAH, and try to find a new mechanism of cPAH as well as new methods to prevent and control the morbidity and the mortality of cPAH.

充血性肺动脉高压（cPAH）是先心病常见危重并发症之一，其主要发病机制是肺充血导致肺血管平滑肌增殖、血管重构。GPR91是新近发现调控血管生长和功能的膜受体。前期研究基础表明激活肺动脉GPR91后血管平滑肌磷脂酰肌醇3-激酶/蛋白激酶B (PI3K/AKT) 活化，进而引起血管平滑肌增殖、动脉重构，我们推测在cPAH患者中，GPR91同样通过激活PI3K/AKT进而导致肺动脉平滑肌增殖、动脉重构，从而在cPAH的形成中发挥重要作用。本研究拟观察在cPAH动物模型及离体平滑肌细胞培养中GPR91对肺动脉平滑肌细胞PI3K/AKT及增殖、分化、凋亡的影响；进一步研究其影响血管平滑肌增殖、分化、凋亡分子机制；同时，利用GPR91基因敲除cPAH模型，观察敲除该基因对cPAH发生发展的影响。本课题研究具有源头创新性，可为先心病患儿cPAH的防治提供新的靶标。

充血性肺动脉高压（cPAH）是先心病常见危重并发症之一，其主要发病机制是肺充血导致肺血管平滑肌增殖、血管重构。GPR91是新近发现调控动脉生长和重构的膜受体。前期研究表明激活肺GPR91后血管平滑肌肾素-血管紧张素-醛固酮系统（RAAS）表达上调，进而血管平滑肌增殖，动脉重构，提示GPR91可能通过激活RAAS进而导致肺动脉重构，从而在cPAH的形成中发挥重要作用。本研究发现观察在cPAH动物模型及离体平滑肌细胞培养中GPR91对肺动脉RAAS及平滑肌的增殖具有激活影响； GPR91对RAAS及平滑肌增殖、分化、凋亡、迁移均有促进影响；进一步研究发现影响血管平滑肌变化、动脉重构的分子机制与PI3K/AKT有关；同时，利用GPR91基因敲除cPAH模型，观察到敲除该基因对cPAH具有减轻肺动脉平滑肌增殖的影响。本课题研究具有源头创新性，可为先心病患儿cPAH的防治提供新的靶标。