前列腺素E2受体EP4通过AMPK调控线粒体自噬在减轻糖尿病心肌病损伤中的作用及机制研究

新近研究表明，线粒体自噬在心肌细胞抵抗糖尿病对其损伤中起重要作用。但具体分子机制不明确。我们预实验发现，前列腺素E2受体EP4,在心肌细胞中可通过调节AMPK表达及活性，对线粒体自噬进行调控。糖尿病刺激下，EP4缺失小鼠心室功能障碍，心脏结构性改变，心肌肥厚及纤维化，心肌细胞ROS水平上升，此外，心肌中AMPK表达量及活性降低，并伴随有线粒体自噬相关蛋白表达降低。因此，我们推测，糖尿病心肌中EP4缺失，抑制AMPK表达及活性，其进一步减弱线粒体自噬，可能是导致高糖对心肌损伤加重的关键原因。而上调EP4，促进AMPK表达及活性进而提高线粒体自噬可能是抵抗糖尿病心肌损伤的有效手段。本项目拟在在体心脏与离体细胞模型上探索EP4通过AMPK调节线粒体自噬的分子机制，为防治糖尿病心肌病提供新思路。

Mitophagy is recently identified as a powerful regulator in protecting against diabetic cardiomyopathy. However, the detailed mechanism remains unclear. Our preliminary finding suggested that prostaglandin E receptor subtype 4 regulates mitophagy through mediating AMPK signaling. Diabetic EP4-/- mice showed cardiac dysfunction, together with cardiac hypertrophy and fibrosis, and elevated intracellular ROS production, which was attributed to decreased AMPK phosphorylation, and reduced mitophagy. Therefore, we hypothesized that severe diabetic cardiomyopathy in EP4 deficient mice was due to impaired AMPK-mediated mitophagy; while increased EP4 could possibly attenuate damages in diabetic cardiomyocytes through enhancement of AMPK signaling and improvement of mitophagy, which results in alleviating diabetic cardiomyopathy. This project intends to use type II diabetes model in both Sprague-Dawley rats and EP4-/- mice, and also apply primary cardiomyocytes and H9C2 cells to investigate the molecular mechanisms of EP4 in AMPK-mediated mitophagy signaling axis. The proposed studies in this project will largely improve our understanding of EP4 function in mitophagy and may contribute to development of novel and optimal therapies in treating diabetic cardiomyopathy.