Cav-1通过DNA甲基化调节香烟烟雾致肺动脉高压模型肺血管重塑的作用及其机制研究

Smoking (including passive smoking) is well known as the most important risk factor for chronic obstructive pulmonary disease（COPD). However, the mechanism of COPD or COPD-induced pulmonary hypertension（COPD-PH) caused by smoking that how smoking attribute to COPD-PH remains unclear. Our group found that cigarette smoke and nicotine up-regulate transient receptor potential canonical channels (TRPC) protein expression, basal calcium and store-operated Ca2+ entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs), and eventually lead to the development of vascular remodeling and PH. Caveolin-1 (Cav-1) is a structural and functional protein that locate in cell membranes. It’s reported that the expression and epigenetic changes of Cav-1 played an important role in the development of multiple diseases. Our preliminary study showed that Cav-1 protein expression was up-regulated and the methylation of Cav-1 was decreased in lung tissue from cigarette smoke-induced pulmonary hypertension in rat model. Based on that, we purpose that cigarette smoke and nicotine-induced increase of basal calcium and SOCE in PASMCs may cause abnormal proliferation and migration of PASMCs through the regulation of Cav-1 protein expression and epigenetic changes, and finally lead to pulmonary hypertension. Thereby we hope that understand the mechanism of cigarette smoke-induced pulmonary hypertension would provide supports on the prevention, clinical treatments and drug developments for this disease.

吸烟（包括被动吸烟）是目前公认的慢性阻塞性肺疾病（COPD）重要危险因素。然而，目前关于吸烟导致COPD或COPD致肺动脉高压（PH）的发病机制仍不十分清楚。我们以往研究发现香烟烟雾暴露及尼古丁可通过升高瞬时受体电位通道（TRPC）蛋白，促进肺动脉平滑肌细胞钙离子浓度升高及细胞增殖，并最终导致肺血管重塑、肺动脉高压的发生。小凹蛋白1(Cav-1)是位于细胞胞膜上的一种结构和功能蛋白，Cav-1表达及其表观遗传改变参与多种疾病发生发展过程。我们前期研究也发现，香烟烟雾致肺动脉高压大鼠肺组织中Cav-1表达上调，且其甲基化水平明显降低。因此我们提出了香烟烟雾及尼古丁通过Cav-1表达及其表观遗传改变调节肺动脉平滑肌细胞内钙稳态，引起细胞异常增殖及收缩、血管重塑，并最终导致PH发生的研究假设。希望藉此研究进一步揭示香烟烟雾致PH发病机制，为该病防治提供新的理论依据。

肺动脉高压（PH）是一种罹患致死疾病，其主要的病理生理表现为肺血管重塑。深入研究PH肺血管重塑的发病机制具有重要的意义。因项目实施过程中，发现CAV-1可能并不通过DNA甲基化参与PH肺血管重塑过程。因而调整研究内容为:1>骨形态发生蛋白4（BMP4）在慢性缺氧性肺动脉高压(CHPH)肺血管重塑的作用及机制;2>BMP9/BMPR2/smad信号通路在博来霉素（BLM）诱导的肺纤维化相关肺动脉高压肺血管重塑的作用及机制研究。研究结果显示BMP4通过上调ROS参与CHPH发病过程，丹参酮IIA可通过下调BMP4及ROS对CHPH大鼠模型产生治疗作用。通过体内体外实验，明确BMP9/BMPRII/SMAD信号通路通过调节内皮细胞功能及凋亡参与BLM诱导的PF-PH、肺血管重塑病理生理全过程。同时还证实rhBMP9蛋白对BLM诱导的PF-PH大鼠模型具有治疗作用。通过提出BMP9治疗肺纤维化相关肺动脉高压的新机制，为有效靶向治疗肺纤维化相关肺动脉高压治疗药物提供新的思路。