AGGF1在糖尿病下肢血管功能障碍中的作用及机制研究

糖尿病下肢血管功能障碍是糖尿病患者常见并发症之一。血管生成因子AGGF1作为分泌蛋白具有多种生物学功能，但是否参与糖尿病下肢血管功能障碍尚不明确。预实验结果显示：链脲菌素诱导的1型糖尿病和2型糖尿病db/db小鼠，行股动脉结扎后血管组织及高糖处理的内皮细胞中AGGF1表达降低；AGGF1蛋白可改善链脲菌素诱导糖尿病小鼠后肢股动脉结扎术后的血流再灌。RNA seq分析显示AGGF1调节线粒体功能相关基因（PINK1和PDK4等）表达；这些基因的启动子含转录因子MEF2c结合位点；MEF2c过表达可抑制由AGGF1下调导致的线粒体功能相关基因表达量降低。因此，本项目将从整体动物和细胞水平，验证科学假说：AGGF1通过MEF2c调节线粒体功能基因水平，改善高糖/糖尿病导致的线粒体功能异常，抑制糖尿病下肢血管功能障碍。本项目可望揭示糖尿病下肢血管功能障碍新机制，为相关疾病防治提供新靶点和思路。

Diabetic peripheral artery dysfunction is one issue for diabetes complications. Although secretory growth factor AGGF1 has multiple biological function, it is not clear whether it is involved in the diabetic peripheral artery dysfunction. Our results showed that, in both type 1 diabetic mouse by Streptozotocin (STZ) treatment and db/db mouse, one genetic type 2 diabetic mouse, the reduction of AGGF1 was caused by femoral artery ligation. High glucose causes the decline of AGGF1 expression in HUVECs. And administration of AGGF1 protein can promote the perfusion in the hindlimb ischemic model of type 1 diabetic mouse induced by STZ injection. The results from RNA sequencing showed that the reduction of PINK1 and PDK4 expression, which are related to the mitochondrial function. Fine-mapped analysis showed the binding sites for MEF2c are identified along the promoters for PINK1 and PDK4. Overexpression of MEF2c abolishes the reduction of PINK1 and PDK4 expression caused by high glucose. In summary, we will perform both of in vivo and in vitro experiments to confirm the mitochondrial function is regulation by AGGF1 via MEF2c-dependent pathway, preventing the endothelial mitochondrial dysfunction in diabetic peripheral artery disease.