Endophilin A2维持血管内皮功能和血压稳态的分子机制研究

NO/ROS失衡是心脑血管疾病发生的重要原因。我们前期发现全身性敲除endophilin A2促进eNOS泛素化降解，同时提高NADPH氧化酶活性，导致内皮细胞NO/ROS产生失衡，诱导小鼠血压升高。但具体机制不清。本研究拟首先采用内皮特异性基因敲除和转基因小鼠，阐明内皮细胞的endophilin A2影响eNOS蛋白稳定性和NADPH氧化酶活性的分子机制，揭示endophilin A2调控血管功能和结构进而维持血压稳态的作用机理。进一步在明确endophilinA2结合eNOS以及NADPH氧化酶亚基关键结构域的基础上，合成蛋白多肽，探讨其对血管功能和血压的影响。该工作将揭示endophilinA2在维持NO/ROS平衡和血压稳态中的关键作用，提出endophilinA2是eNOS稳定分子和NADPH氧化酶抑制分子的新观点，同时为从蛋白多肽角度探讨改善血管功能失衡的新手段提供理论依据。

The imbalance of nitrite oxide (NO)/reactive oxygen species (ROS) contributes to the development of cardiovascular diseases. Our previous work showed that global knockout of endophilin A2 induces NO/ROS imbalance through promoting eNOS ubiquitin-dependent degradation and upregulating the activity of NADPH oxidase, and thus increases the mouse blood pressure. But the mechanism is not clear. Basis on these observation, our present project aims to clarify the mechanism how endophilin A2 stabilizes eNOS protein and increases the activity of NADPH oxidase, and thus unveil the critical role of endophilin A2 in maintaining the vascular homeostasis and blood pressure using endophilin A2 gene knockout and transgenic mice. Moreover, we will investigate the key interaction domains in endophilin A2 with eNOS and the subunits of NADPH oxidase, and evaluate the effect of protein peptide on vascular function and blood pressure. Our study will reveal the essential role of endophilin A2 in regulation of NO/ROS production and vascular homeostasis, and provide the evidence that modulation of endophilin A2 expression may be a novel therapeutic stratage for vascular dysfunction during the development of cardiovascular diseases.