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

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.

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。

糖尿病性心肌病是一种特殊的心肌疾病，会导致糖尿病患者心衰死亡的高风险。心脏中超过95％的ATP产生来自线粒体中长链脂肪酸β-氧化。因此，心肌脂肪酸代谢对于维持正常心脏功能以及对各种疾病压力（如糖尿病）的反应至关重要。前列腺素E2受体EP4在心肌细胞中广泛表达，并已证明在心脏功能中起重要作用。然而，EP4在调节心肌脂肪酸代谢中的功能仍然未知。我们的研究表明，EP4缺失小鼠表现出心脏结构性改变，例如心室功能障碍，心肌肥厚及瘢痕纤维化，线粒体结构及心功能异常。FOXO1/CD36信号介导的心肌脂肪酸摄取能力下降及心肌能量ATP合成受阻，导致心脏能量被剥夺，导致心肌维持正常工作的能量供应严重缺乏，可能是引起高脂对心肌损伤加重的关键原因。而药理性激活EP4受体增强心肌细胞对游离脂肪酸的摄取及氧化作用，激活能量ATP合成，可能是抵抗糖尿病性心肌损伤的有效手段。本研究表明，EP4通过FOXO1/CD36信号传导紧密协调心脏脂肪酸摄取和线粒体脂肪酸β-氧化的速率。我们的研究为EP4与心脏脂肪酸代谢之间的联系提供了证据，并进一步指出，EP4受体可能是调节脂肪酸代谢和抑制糖尿病心脏组织特异性功能损害的潜在靶点。