大气PM2.5通过Notch信号通路调控脂质水平的机制及其在冠心病发生与进展中的作用

Exposure to atmospheric PM2.5 can induce lipid levels disorder and the formation of foam cells, and further affect the onset and development of coronary heart disease (CHD), however, the underlying mechanism remains unclear. Recent studies show that Notch ligands have lipid combination domains which are responsible for regulating lipid levels. Our previous studies on rat model have demonstrated that exposure to atmospheric PM2.5 can affect the blood lipid levels and the expression of downstream gene Hes-1in Notch signaling pathways. Moreover, the serum TG levels was significantly decreased when Notch signaling pathway was suppressed.Therefore, we hypothesize that the atmospheric PM2.5 may mediate Notch signaling pathways to regulate lipid levels, which plays an important role in the onset and development of CHD. The present study will expose rats, THP-1 macrophage, CHD animal model and cell model to atmospheric PM2.5 to investigate the regulating effects of ambient PM2.5 on lipid level by the Notch signaling pathways and their roles in the onset and development of CHD through such techniques as Notch signaling pathway suppression, immune co-precipitation and specific Notch signaling pathway genes silence. The present work will provide a new insight into the pathogenic mechanisms underlying lipid levels disorder influenced by atmospheric PM2.5 and will be of great significance to identify new targets to prevent and cure CHD.

大气PM2.5暴露可导致机体脂质水平异常，诱发泡沫细胞形成，影响冠心病的发生与进展，但作用机制尚不清楚。近期的研究显示Notch配体上存在脂质结合域，可调控脂质水平。我们前期研究发现大气PM2.5暴露可影响大鼠血脂水平和Notch信号通路下游基因Hes-1表达水平，且Notch信号通路被抑制时PM2.5暴露大鼠血清中TG水平显著降低。据此我们推测大气PM2.5可通过Notch信号通路调控脂质水平在冠心病的发生与进展中起作用。本项目拟通过给予大鼠和THP-1源巨噬细胞、冠心病动物模型和细胞模型大气PM2.5暴露，采用Notch信号通路抑制、免疫共沉淀和靶向沉默Notch信号通路基因等技术，从体内-体外角度阐明大气PM2.5通过Notch信号通路对脂质水平的调控机制及其在冠心病发生和进展中的作用。本研究有望揭示大气PM2.5影响脂质水平的一种新机制，也将为冠心病的防治提供新靶点。

大气PM2.5污染已成为冠心病的重要致病因素和致死因素。大气PM2.5暴露可导致机体脂质水平异常，诱发泡沫细胞形成，导致动脉粥样硬化，促使冠心病的发生与进展，但其作用机制尚不清楚。Notch通路是体内重要的信号通路，近年来研究发现Notch通路分子可能通过与脂质结合调控机体脂质水平，这可能是大气PM2.5影 冠心病发生与进展的新机制。本课题从体内-体外角度阐明大气PM2.5通过Notch信号通路对脂质水平的调控机制及其在冠心病发生和进展中的作用。体内研究结果表明PM2.5暴露可导致正常大鼠和动脉粥样硬化大鼠血脂水平升高，上调大鼠心脏和动脉血管中Notch信号通路的表达，进而干扰脂代谢关键基因ABCA1、LDLR、SR-BI和SREBP2的表达，引起大鼠脂代谢紊乱，导致或加重大鼠动脉粥样硬化的发生与进展，且抑制Notch信号通路后，大鼠血脂水平得到改善。体外研究结果表明大气PM2.5暴露可激活Notch信号通路，导致巨噬细胞和泡沫细胞中脂代谢相关基因ABCA1、LDLR、SR-BI和SREBP2表达量改变，促进了巨噬细胞和泡沫片细胞的脂质蓄积；抑制Notch信号通路能够降低大气PM2.5所造成的脂质蓄积，从而减缓动脉粥样硬化的发生和进展，且这一作用是由Notch信号通路调控巨噬细胞和泡沫细胞脂代谢关键基因ABCA1、LDLR、SR-BI和SREBP2的表达所介导的。本研究提示PM2.5通过调控Notch信号通路来影响脂代谢关键基因的表达，导致脂质蓄积、脂代谢紊乱进而影响动脉粥样硬化的发生与发展，这是大气PM2.5污染影响冠心病发生与发展的重要机制之一。本研究揭示了一种新的大气PM2.5影响脂质水平的分子机制，可为防治PM2.5所致动脉粥样硬化提供重要的科学依据，也将为冠心病的防治提供新靶点。