长期慢性缺氧下缺氧诱导因子1α动态改变影响心脏能量代谢的机制研究

多种疾病的患者处于长期慢性缺氧状态，如紫绀先心病等。此类患者会有不同程度的心功能受损。以往的研究更多关注于慢性缺氧诱导肺动脉高压造成的心功能异常。我们前期在小鼠模型上发现慢性缺氧下心脏能量代谢发生适应性改变，从脂肪酸代谢转变为以氧气利用效率更高的葡萄糖代谢为主，从而维持慢性缺氧下的心脏ATP生成和相对正常的心功能。但到达一定节点以后，这种适应性代谢模式出现障碍，进而导致心功能衰竭。我们进一步发现心脏适应性代谢的形成和后期障碍中缺氧诱导因子1α（HIF1α）也发生同样的升高和下降的改变。因此，我们提出“HIF1α可能是慢性缺氧下心脏能量代谢从适应到失衡的关键因素”的假说。本研究中我们试图从整合生理学的角度，通过解析胰岛素抵抗和心脏HIF1α的关联，提出慢性缺氧下心脏能量代谢动态改变的机制，从而为改善罹患慢性缺氧患者心功能提供新的可干预的生物靶点。

In clinical practice, there is a group of patients suffering from chronic hypoxia, such as patients with cyanotic congenital heart disease. Accumulating evidence shows that these patients have various degrees of impaired cardiac function. Previous studies mainly focus on the secondary cardiac dysfunction caused by hypoxia-induced pulmonary hypertension. In our preliminary experiments, we found that the heart undergoes switch from fatty acid metabolism to glucose metabolism under chronic hypoxia. This adaptive metabolism improves cardiac oxygen utilization efficiency to maintain sufficient ATP production and normal cardiac function under chronic hypoxia. However, after reaching a turning point, adaptive metabolism is impaired and cardiac functions are decreased. Furthermore, we found that the initiation and subsequent termination of adaptive metabolism under chronic hypoxia are accompanied by similar dynamic changes in hypoxia-inducible factor 1α (HIF-1α). Thus, we hypothesize that HIF-1α might play an important role during this process. In this study, we will analyze the communication between endocrine system and cardiovascular system to explain the dynamic changes of HIF-1α under chronic hypoxia as well as its influences on cardiac metabolism, which might offer a novel therapeutic target to improve cardiac function for the chronically hypoxic patient.