ACE2对HMGB1的调控在糖尿病心梗后心力衰竭中的保护作用及机制研究

糖尿病患者在围术期易发心肌梗死，如何减轻心肌损伤、防止心衰发生是临床研究的重要方向。高迁移率族蛋白1（HMGB1）被证实是糖尿病发展到心梗以及心衰过程中的关键环节。我们前期研究表明，血管紧张素转换酶2（ACE2）能有效抑制心梗所致的HMGB1释放、改善心功能。因此，ACE2对心肌HMGB1的调控可能是其对抗糖尿病心梗后心衰的重要机制之一。本课题拟用ACE2基因过表达小鼠，观察ACE2在糖尿病及并发心梗期对HMGB1释放、炎性介质、心肌损伤等的影响，通过药物双向干预HMGB1表达，进一步明确HMGB1在ACE2对抗糖尿病心梗后心衰中的作用；采用迷走神经切断、受体阻滞等手段，从分子、细胞、组织、整体水平探讨ACE2对糖尿病心梗后心衰过程中HMGB1的调控机制。本研究将有助于从HMGB1这一新视点深入探讨ACE2对糖尿病心梗后心衰的保护机理，为糖尿病患者在围术期的心脏不良事件的防治提供新思路。

Diabetes mellitus (DM) patients are susceptible for myocardial infarction(MI) during perioperative period. It is an important research direction to limit myocardial injury and improve heart function for better clinical outcomes. The high mobility group box1 (HMGB1) has been shown to be a key link between diabetes and MI-induced heart failure (MI-HF). Our previous work has proven that ACE2 can significantly inhibit the excessive HMGB1 release and improve heart function when MI occurs. Therefore, HMGB1 may be a pivotal target which is regulated by ACE2 in DM-HF setting. In the current project, ACE2-transgenic mice were administrated to explore the effects of ACE2 and its modulation on cardiac HMGB1 release, inflammatory cytokines and myocardial injury indicators.Relevant reagents are administrated to interfere the expression of HMGB1 to explore the role of HMGB1 in ACE2-mediated preotective effects in DM-HF. Vogotomy and antagonists of associated receptors were used to further investigate the role of HMGB1 in the regulation of ACE2.This project will be beneficial for further exploration of the protective mechanisms of ACE2 on the DM-HF condition, and offer new insights and new targets for the prevention of the perioperative cardiovasular events for diabetes patients.