转录因子KLF5在缺氧性肺血管重构中的作用及其分子机制

Pulmonary arterial remodeling induced by chronic hypoxia is the important pathological alteration of pulmonary arterial hypertension in patients with chronic obustructive pulmonary disease, which has a serious effect on the prognosis of the patients. So far, the underlying mechanism remains uncertain. Krüpper like factor (KLF) 5, a kind of zinc finger protein,is an important transcript factor. It has been demonstrated to be involved in the regulation of several biological behaviour in systemic arterial smooth muscle cell (ASMC) and some cancer cells. Recent study suggested that KLF5 increased the abnormal proliferation via cyclin D1 and cyclin B1, inhibited the apoptosis via survivin and caspase, promoted the migration in systemic ASMC in the process of stenosis induced by balloon injury and atherosclerosis.However, it is unclear whether KLF5 regulates the proliferation and apoptosis of pulmonary ASMC, and promotes the migration by the similar mechanism in pulmonary arterial remodeling induced by chronic hypoxia.The current research is to investigate the role of KLF5 in the abnormal proliferation,apoptosis and migration of pulmonary ASMC under hypoxic condition, and explore the role of KLF5 in the process of hypoxic pulmnoary arterial remodeling. This study will provide scientific experimental data for further clarifying the pathogenesis of hypoxic pulmonary arterial hypertension and finding new therapeutic target point.

慢性缺氧引起的肺血管重构是慢性阻塞性肺疾病患者并发肺动脉高压的重要病理学基础，严重影响患者的预后，其机制至今尚未完全阐明。锌指蛋白Krüpper like factor 5(KLF5)是一种重要的转录因子，参与调控体循环血管平滑肌细胞、肿瘤细胞的多种生物学行为。近期研究发现，在球囊损伤、动脉粥样硬化致血管再狭窄过程中，KLF5通过周期蛋白（cyclin）D1、B1加速平滑肌细胞的异常增殖，通过survivin等抑制平滑肌细胞凋亡，同时促进平滑肌细胞的迁移。但是，在慢性缺氧导致的肺血管重构机制中，目前尚不清楚KLF5是否通过cyclin、survivin等调控细胞的增殖、凋亡，以及对细胞迁移的影响。本项目拟探讨缺氧条件下，KLF5对肺动脉平滑肌异常增殖、凋亡、迁移调控及机制，研究KLF5在缺氧性肺血管重构中的作用，为进一步阐明缺氧性肺动脉高压的发病机制及新的可能治疗靶点提供科学的实验资料

慢性缺氧引起的肺血管重构是缺氧性肺动脉高压的重要病理学基础，严重影响患者的预后，其机制至今尚未完全阐明。锌指蛋白 Krüpper like factor 5(KLF5)是一种重要的转录因子，参与调控体循环血管平滑肌细胞、肿瘤细胞的多种生物学行为。而KLF5在缺氧肺动脉高压的作用尚不清楚。本研究探讨缺氧条件下，KLF5 对肺动脉平滑肌异常增殖、凋亡、迁移调控及机制，探讨 KLF5 在缺氧性肺血管重构中的作用，进一步阐明缺氧性肺动脉高压的发病机制及寻找新的可能治疗靶点。研究结果表明，缺氧大鼠肺动脉平滑肌增殖增加、凋亡减少，血管重构形成；缺氧引起肺动脉平滑肌细胞（HPASMC）增殖和迁移能力增加、细胞凋亡减少。缺氧诱导大鼠肺动脉及HPASMC高表达KLF5。沉默KLF5可以显著降低缺氧大鼠的肺动脉压力、改善血管重构和右心室肥厚。KLF5与HIF-1α直接结合，沉默KLF5可以下调HIF-1α水平，过表达KLF5上调HIF-1α表达，而下调HIF-1α不影响KLF5的表达。KLF5-HIF-1α轴通过介导cyclin B1、cyclin D1、survivin、bax/bcl-2、caspase-3 和caspase-9表达变化调控HPASMC的生长和迁移。表明KLF5-HIF-1α轴在缺氧性肺动脉高压的发病机制中发挥重要作用。除原定研究内容之外，进一步探讨了KLF5在肺癌细胞中的调控作用及其机制。结果发现：KLF5在缺氧A549细胞中高表达，并介导了缺氧诱导HIF-1α的过程，KLF5-HIF-1α轴在肺癌细胞活力、克隆能力、增殖和凋亡中发挥重要调控作用；还发现氟伐他汀可抑制缺氧环境血管内皮细胞的增殖并促进凋亡，可能在肿瘤治疗中发挥作用。还探讨了中药提取物槲皮素通过TrKA信号通路缓解肺动脉高压及减轻肺血管重构的具体机制。