Endophilin A2下调在代谢紊乱导致内皮功能障碍中的作用及机制

我们前期工作发现endophilin A2与eNOS相互结合，下调endophilin A2降低eNOS表达，高脂血症endophilinA2表达减少，提示endophilin A2可能是高脂血症诱导内皮功能障碍的关键因素，但机理不清。本研究拟首先揭示endophilin A2结合eNOS分子机制，并采用基因敲除和转基因小鼠，明确endophilin A2对内皮依赖性舒张反应的调控机制及其表达变化在代谢性疾病诱导内皮功能障碍中的作用。进一步根据endophilin A2与eNOS结合的结构域特点，合成蛋白多肽并探讨其对代谢性疾病诱导内皮功能障碍中的影响。该研究工作将较系统地认识endophilin A2表达下调诱导内皮功能障碍的的分子机制，为评估endophilin A2否可作为改善内皮功能障碍的新靶点提供提供实验室基础，同时为从蛋白多肽角度寻找改善内皮功能障碍的新手段提供依据。

Our previous work has revealed that endophilin A2 can interact with eNOS protein, knockdown of endophilin A2 decreased eNOS expression and NO production. In addition, hyperlipidemia downregulated endophilin A2 expression, these findings suggested that endophilin A2 downregulation may be the critical contributor to endothelial dysfunction during hyperlipidemia, however, the underlying mechanisms are not understood. In this study, we will investigate the molecular mechanism how endophilin A2 regulates eNOS stability at first. Moreover, we will study the effects of endophilin A2 on endothelial dysfunction induced by hyperlipidemia and hyperglucomia by using endophilin A2 gene knockout and transgenic mice. Furthrmore, we will evaluate the effects of protein peptide on endothelial dysfunction. Our study will recognize the important role of endophilin A2 in the regulation of eNOS expression and endothelium-dependent vasorelaxation and provide the evidence that modulation of endophilin A2 expression may be a nove therapeutic stratage for endothelial dysfunction during the development of cardiovascular diseases.