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

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.

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。

血管紧张素转换酶2（ACE2）作为血管紧张素转换酶（ACE）的同源物，能够产生一系列对抗经典肾素-血管紧张素-醛固酮系统（RAS）的效应，包括抗炎作用及器官保护作用。本研究旨在研究ACE2对高迁移率族蛋白（HMGB1）这一重要炎性介质的调控在糖尿病心梗后心力衰竭中的保护作用及机制。研究结果表明：1.运用HMGB1特异性拮抗剂下调HMGB1表达水平后，能显著减轻糖尿病合并心梗所引起的心肌损伤，减少心肌纤维化面积、心肌组织中TNF-α、IL-6等炎症因子水平，并上调ACE2的表达；2.心肌过表达ACE2（AAV9-ACE2）能够有效减少糖尿病心肌梗死过程中HMGB1的释放，显著减轻心肌损伤，缩小心肌纤维化面积、改善心功能、降低血清TNF-α、IL-6等炎症因子水平；单侧迷走神经切断后，以上效应被完全逆转；表明ACE2对HMGB1的调控以及心肌损伤的保护作用有赖于迷走神经的完整性；3.使用α7乙酰胆碱能受体阻断剂后，能够显著逆转AAV9-ACE2对糖尿病心肌梗死的心肌保护作用，包括心肌纤维化面积增加、心功能恶化、血清TNF-α、IL-6等炎症因子水平上升、HMGB1表达增加，进一步说明ACE2是通过胆碱能抗炎通路实现对HMGB1的调控以及在糖尿病心肌梗死模型中的保护作用。综上，ACE2过表达通过胆碱能抗炎通路调控HMGB1减轻糖尿病心肌梗死所致的心肌损伤。