Endophilin A2通过促进血管新生改善缺血性心肌损伤及机制研究

Endophilin是一类含SH3结构的蛋白，其在心血管系统的功能尚不清楚。我们发现心血管系统主要表达endophilinA2亚型，在缺血性心肌和骨骼肌中其表达下调。EndophilinA2缺失降低VEGFR2蛋白表达，但mRNA水平无变化，且两蛋白间存在相互作用。敲除endophilinA2显著抑制小鼠后肢缺血后血流恢复，提示endophilinA2可能是调控VEGFR2蛋白稳定性和血管生成的关键分子。在此基础上，本研究拟采用endophilinA2敲除和内皮特异性转基因小鼠，制备心肌缺血模型，首先明确endophilinA2对缺血性心肌损伤和血管新生的影响，并进一步从调控VEGFR2蛋白稳定性的角度揭示endophilinA2调控血管新生的分子机制。该工作将从调控血管新生的角度阐明endophilinA2的新功能，为评估endophilinA2是否是防治缺血性疾病的新靶点提供实验依据。

The endophilin A proteins are a family of src homology 3 (SH3) domain-containing proteins, but their functions in cardiovascular system remain unknown. Our previous study showed that endophilin A2 was the most abundantly expressed isoform compared with Endophilin A1 and Endophilin A3 in cardiovascular tissues and was significantly decreased in ischemic cardiac and skeletal muscle tissues. Moreover, we found that endophilin A2 interacted with VEGFR2. Knockout of endophilin A2 decreased VEGFR2 protein expression, but had no effect on VEGFR2 mRNA expression. Compared with wide type mice, blood flow and VEGFR2 expression in ischemic limbs was markedly impaired in endophilin A2 knockout mice, indicating endophilin A2 may play an important role in regulating VEGFR2 protein stabilization and angiogenesis. The present study aims to clarify the functional role of endophilin A2 in angiogenesis of myocardial infarction with endophilin A2 knockout mice or endothelium-specific transgenic mice. Furthermore, we will investigate the mechanisms by which endophilin A2 regulates VEGFR2 protein expression and angiogenesis. This work will provide evidences that endophilin A2 may play a critical role in regulating angiogenesis, suggesting endophilin A2 may be a novel therapeutic target for the treatment of ischemic diseases.