nAchRs-PI3K/Akt-TRPC信号通路在香烟烟雾暴露致PAH中的调控机制

PAH is an important complication of COPD and the serious cause of the increased mortality rate of right heart failure. About 80-90% of patients with COPD are associated with smoking, and 25% of these patients have high pulmonary artery pressure in the early phase. It is known that smoking can promote the pulmonary artery reconstruction which is directly involved in the formation of PAH, but the mechanism is unknown. We found that the basal Ca2+ and SOCE were increased, the expression of nAchRs, TRPC and P-Akt were changed when the PASMCs were pretreated with the nicotine. According to the basic researchs and clinical treatments, we want to find the mechanisms about the nAChRs combinated with nicotine, activation of PI3K /Akt pathways, raised expressions of TRPC and related cell cycle proteins and the increased calcium flows in the study of smoking model animal, related cell protein expression, intracellular free calcium and signaling pathways.

肺动脉高压(PAH)是慢性阻塞性肺疾病(COPD)重要合并症并最终引发右心衰造成死亡率提高.国内外约80-90%COPD患者皆与吸烟有关,其中25%的患者早期已有严重的肺动脉压力升高.研究已知吸烟导致肺动脉平滑肌细胞(PASMC)的增殖,促进肺血管重建,直接参与PAH的形成,但机制未明.本课题组预实验发现尼古丁处理大鼠PASMCs, 胞内的基础Ca2+,SOCE增高,且nAchRs,TRPC和P-Akt表达改变.本研究从香烟烟雾暴露大鼠模型的建立,尼古丁刺激下原代培养PASMCs中nAchR-PI3K/Akt-TRPC相关信号通路的研究,胞浆游离钙测量等方面,明确香烟烟雾中的尼古丁与PASMCs上nAChRs结合,激活PI3K/Akt通路,上调TRPC和相关细胞周期蛋白cyclinD1/E的表达,增加细胞钙内流,促使血管收缩及细胞增殖,诱发PAH的机制.从而为基础研究和临床治疗提供新依据.

本研究从香烟暴露动物模型-细胞各相关蛋白表达-胞浆游离钙水平-胞内信号通路分子表达等方面,明确尼古丁与PASMCs 上nAChRs 结合,激活PI3K/Akt 通路,上调TRPC 和相关细胞周期蛋白,增加细胞钙内流,促使血管收缩以及细胞增殖,诱发PAH 的机制,为基础研究和临床治疗提供新依据和新靶点.