早老蛋白-1促进线粒体分裂在缺氧性肺血管重构中的分子机制研究

Pulmonary arterial hypertension (PAH) threatens human health seriously, which is characterized by progressive remodeling of the distal pulmonary arteries, therefore, it is significant to find the key molecule regulating pulmonary vascular remodeling to be intervened. The applicant recently found presenilin-1 (PSEN1) was induced by hypoxia and could promote the increased proliferation and reduced senescence induced by hypoxia in the pulmonary arterial smooth muscle cells and hypoxia induced pulmonary vessel thickening, and pulmonary vascular remodeling was associated with mitochondria fission. Nevertheless, how PSEN1 regulates the dynamic process of mitochondria fission and pulmonary vascular remodeling remains unclear. By means of PSEN1 conditional knockout mice, we demonstrated the regulation of PSEN1 in the proliferation and senescence of pulmonary smooth muscle cell under tissue and cell levels; we determined the changes of mitochondria fission and fusion effected by PSEN1 deletion and demonstrated the molecular mechanism of the regulation of PSEN1 in the proliferation and senescence of pulmonary arterial smooth muscle cells by mediating the mitochondrial dynamic dysfunction via mitochondrial fission protein DRP1; by the lung targeting liposome loading PSEN1 specific inhibitor, we tested the preventive and therapeutic role of PSEN1 in the disease of pulmonary vascular remodeling, which provide a novel idea in the prevention and treatment of pulmonary arterial hypertension.

肺动脉高压严重威胁人类生命健康，以远端肺动脉进行性重构为主要特征，因此寻找调控肺血管重构的关键分子加以干预对肺动脉高压的治疗具有重要意义。申请人前期发现缺氧诱导早老蛋白-1（PSEN1）的表达，PSEN1会促进缺氧导致的肺动脉平滑肌细胞增殖增加、衰老减少及缺氧性肺动脉中层增厚，并且肺血管重构与线粒体分裂有关，然而PSEN1如何调控线粒体分裂的动态过程以及缺氧性肺血管重构尚不明确。为此，本项目拟通过构建的PSEN1条件性敲除小鼠模型，在组织和细胞水平明确PSEN1在肺动脉增殖与衰老中的作用；探索PSEN1缺失对线粒体融合与分裂动态变化的影响，阐明PSEN1通过介导线粒体分裂蛋白DRP1造成线粒体动态失衡，从而促进肺动脉平滑肌增殖与抑制肺动脉平滑肌衰老的分子机制；并用肺靶向脂质体包裹PSEN1特异性阻断剂，验证PSEN1对缺氧性肺血管重构疾病的防治作用，为肺动脉高压的预防与治疗提供新思路。

肺动脉高压是一种以远端肺动脉进行性重构为主要特征的恶性心血管系统疾病。线粒体稳态失衡导致的肺血管重构特别是肺动脉平滑肌细胞衰老与增殖异常是肺动脉高压疾病发生的重要病理过程，分子机制不明。我们的研究发现，缺氧诱导早老蛋白-1（PSEN1）的表达，PSEN1会促进缺氧导致的肺动脉平滑肌细胞增殖增加、衰老减少及缺氧性肺动脉中层增厚，然而PSEN1如何调控线粒体分裂的动态过程以及缺氧性肺血管重构尚不明确。我们假设PSEN1通过介导线粒体分裂蛋白DRP1造成线粒体动态失衡，从而促进肺动脉平滑肌细胞增殖与抑制肺动脉平滑肌细胞衰老，引起肺血管重构。发现如下重要结果：1）PSEN1平滑肌特异性敲除小鼠逆转缺氧性肺血管重构；2）PSEN1通过线粒体分裂蛋白DRP1促进肺动脉平滑肌细胞增殖与抑制肺动脉平滑肌细胞衰老过程；3）肺靶向给予PSEN1抑制剂ELN318463能够逆转缺氧引起的肺血管重构。本申请明确PSEN1在缺氧肺血管稳态失衡、重构中的作用和机制，发现治疗肺血管重构相关疾病的靶点。