PM2.5暴露引发RAS成分表达水平上调和血管内皮功能紊乱的分子调控网络研究

I have long been engaged in the basic research to disclose the signaling mechanism involving in cellular stress responses and adverse health effects induced by the environmental risk factors, such as arsenite, ultraviolet and fine particulate matters (PM2.5). Findings from my recent research have revealed the previous unidentified signaling network involving in mediating pro-inflammatory effects in the respiratory system triggered by PM2.5. After getting these results, I extended my research work to the cardiovascular (CV) system due to the potential adverse PM2.5 impact on the progression of various CV diseases. And our primary studies in this field have disclosed the aberrant up-regulation of AGT, ACE and AT1R, the major components of renin-angiotensin system (RAS), contributed largely to the induction of vascular endothelial dysfunction under PM2.5 exposure. Further investigations demonstrated that activation of IRE1α/XBP1s branch of endoplasmic reticulum stress was essential for augmented vascular RAS component expression in response to PM2.5 exposure, whose effects seemed synergistically exerted by the assembly of XBP1s/HIF1α transcriptional complex. Moreover, HO-1 induction inhibited the increasing of RAS components expression in the vascular endothelial cells under the same PM2.5 exposure conditions. The follow-up research work based on these previous clues is expected to disclose the roles of IRE-1a/XBP1s/HIFa pathway activation and HO-1 induction in regulating RAS components augmentation, which will be helpful to elucidate the complex pathological outcomes in the CV system originated from vascular endothelial dysfunction and to search the intervention strategies for alleviating disturbances associated with PM2.5 exposure.

申请人长期开展“环境应激源诱导应激损伤及健康危害的基因表达调控机制”研究工作，近年来在“PM2.5诱发呼吸系统损伤效应机制”研究中取得了系列创新性研究发现。以此为基础，申请人近期又在“PM2.5致心血管系统损伤效应机制”的体内外研究中获得了重要线索，发现了PM2.5暴露能够诱导血管内皮细胞中肾素-血管紧张素系统（RAS）关键成分ANGII、ACE和AT1R表达水平上调并促发后续的血管内皮功能紊乱效应。另外，IRE-1a/XBP1s介导的内质网应激能够偶联HIF1a协同介导上述RAS成分的诱导表达反应；而应激损伤保护因子HO-1能够拮抗RAS成分的诱导表达。本项目拟定基于上述研究线索继续深入探究IRE-1a/XBP1s/HIFa途径和HO-1分别参与调控RAS成分异常扰动和血管内皮损伤反应的信号转导网络，为PM2.5致心血管系统健康危害效应机制研究及损伤防控策略研究提供崭新内容。

申请人长期开展“PM2.5诱导应激损伤及健康危害的基因表达调控机制”研究工作，近年来在“PM2.5诱发呼吸系统损伤效应机制”研究中取得了重要创新性研究发现（Autophagy，2016）。以此为基础，申请人在本项目研究中重点探究了“PM2.5诱发心血管系统损伤效应机制”及内、外源损伤防控策略。.首先我们发现PM2.5暴露能够诱导血管内皮细胞中肾素-血管紧张素系统（RAS）关键成分ANGII、ACE和AT1R表达水平上调。内质网应激IRE-1a/XBP1s活化能够偶联HIF1ɑ协同介导RAS各成分的诱导表达反应；而另一重要转录因子AP-1可在其上游蛋白激酶ERK/p38K催化作用下实现诱导活化进而上调AT1R表达水平。RAS各成分的诱导表达可进一步激活血管内皮粘附分子、趋化因子、氧化应激反应标志性分子并促发血管内皮功能紊乱效应。而应激损伤保护因子HO-1能够通过拮抗HIF1ɑ的聚集和活化进而抑制RAS成分的诱导表达和血管内皮损伤效应。HO-1/HIF1ɑ损伤保护性途径的诱导活化也能够拮抗支气管上皮细胞中VEGF的诱导表达进而发挥对呼吸系统损伤反应的保护性作用。上述结果共同说明：PM2.5不仅能够引发损伤反应，也能够在不同组织中引发以HO-1表达水平上调为主要特征的内源性损伤保护效应。这为我们提供了通过激发内源性保护途径进而防控PM2.5应激损伤效应的重要策略。.针对RAS这一PM2.5诱导心血管系统损伤效应的关键干预靶位，我们先后证实了AT1R拮抗剂缬沙坦和ACE抑制剂依那普利能够显著拮抗PM2.5诱导的血管内皮功能紊乱效应，并提出了应用上述制剂实现PM2.5损伤效应有效干预的实施途径。.在后续拓展性研究工作中，我们采用姜黄这一广谱抗炎和抗氧化应激多酚类中药成分进行PM2.5损伤防控效果及机制研究。结果发现了姜黄预处理能够通过抑制支气管上皮细胞VEGF诱导表达和血管内皮细胞RAS成分诱导表达进而阻断PM2.5引发的呼吸系统和心血管系统功能紊乱效应。这其中涉及姜黄对多种转录因子、血管内皮粘附分子、趋化因子及氧化应激反应效应因子诱导活化反应的拮抗作用。姜黄作为一种食药同源物质，其对PM2.5致健康危害效应的防控作用具有重要挖掘价值。.本项目圆满完成课题研究任务，研究结果为PM2.5致呼吸系统和心血管系统健康危害效应机制及防控策略研究提供了系列创新性发现。