FHL2及自噬在PM2.5暴露诱发糖尿病血管损伤中的作用及机制研究

PM2.5 exposure can lead to systemic inflammation which can also be directly or indirectly lead to diabetic patients with vascular injury, that maybe is the main reason for PM2.5 exposure causing the increase of diabetic vascular injury, but the detailed mechanism remains unclear. It has been recently reported that FHL2 and autophagy are involved in regulation of inflammation and angiogenesis related factors and they may play an important role in the process of vascular injury. Our previous study indicated that PM2.5 exposure could up-regulate the FHL2 expression of vascular tissues in diabetic rat, accompanying by significantly exacerbated vascular injury. The findings in cell levels showed that PM2.5 exposure could upregulate the expression of FHL2, LC3B and beclin-1 in mouse aortic endothelial cells. Based on the above results, the scientific hypothesis we proposed is that PM2.5 exposure significantly exacerbated diabetic vascular injury by inducing FHL2 up-regulation and autophagy production. Therefore we intended to clarify the following issues as: 1) The role of PM2.5 exposure in the exacerbation of diabetic vascular injury; 2) the important function of FHL2 and autophagy in regulation of vascular injury in diabetes after exposure to PM2.5; 3) The molecular mechanisms of FHL2 and autophagy-mediated vascular injury by PM2.5 exposure. So we can provide new targets for treatment of diabetic patients and the intervention strategies for diabetes crowd under PM2.5 exposure.

PM2.5暴露能够引发系统炎症，而炎症反应也可直接或间接导致糖尿病患者血管的损伤，这可能是PM2.5暴露引起糖尿病血管功能障碍增加的主要原因，但其详细的机理尚不清楚。而FHL2及自噬参与炎症反应及血管生成相关因子的调控，在血管损伤过程中发挥重要的作用。我们研究发现PM2.5暴露促进糖尿病大鼠血管组织FHL2的表达，同时伴随有血管损伤的加剧，细胞水平研究发现PM2.5暴露可上调FHL2、LC3B及beclin-1的表达。基于上述研究结果我们拟通过分子生物学、细胞生物学，免疫组织化学等技术，在动物及细胞水平阐明1）PM2.5对糖尿病大鼠炎症和血管重构的作用；2）FHL2及自噬在PM2.5暴露后调控糖尿病血管损伤中的重要作用；3）PM2.5暴露下FHL2及自噬介导血管损伤的分子机制。通过上述科学问题的解答为糖尿病人群的干预治疗提供新的靶点，为PM2.5暴露下糖尿病人群的防控干预策略提供依据。

PM2.5可通过肺组织迅速进入到血液循环后与血管内皮细胞直接接触诱导炎症或损伤，因而，雾霾天气下PM2.5暴露能够引发系统炎症，而炎症反应也可直接或间接导致血管的损伤。我们首先测定北京市区冬季PM2.5组成及质量浓度特征；建立并评价了糖尿病大鼠，PM2.5的急性暴露导致糖尿病大鼠的主动脉血管组织损伤，并促进IL-6及FHL2的表达；小鼠主动脉内皮细胞(MAEC)中，PM2.5通过诱发自噬上调FHL2的表达进而激活NF-κB通路，从而促进炎性因子IL-6的分泌，导致血管损伤。以上结果建立了PM2.5暴露下自噬与FHL2/NF-κB/IL6通路之间的调控关联，阐明FHL2介导的PM2.5诱发炎症和导致血管损伤的分子机制，此外，我们以肺支气管上皮细胞入手，同样发现PM2.5暴露促进炎性因子IL-6的高表达，而FHL2参与了PM2.5暴露的NF-κB及IL-6的调控，这均提示FHL2可能通过参与炎症反应的调控进而在PM2.5诱发的血管损伤过程中发挥重要的作用，为患者人群的干预治疗提供新的靶点，为PM2.5暴露下易感人群的防控干预提供理论依据。