组胺经Erk1/2-mTOR通路抑制急性心梗后的心肌细胞自噬并保护损伤心肌

Acute Myocardial infarction (AMI), one of the complex diseases harmful to human health and life, is the result of lose of myocardial cells caused by ischemia. Its pathogenesis needs to be fully elucidated. How to protect against myocardial cell death is the key strategy to treat AMI. Autophagy in myocardial cell is induced during the earlier stage of myocardial infarction. Overdose of autophagy could result in cell death. The factors contributing to autophagy still need full excavation. In our previous research, histamine was observed to increase both in the patient and mice model of myocardial infarction. And deficiency of endogenous histamine aggravated the death of myocardial cells caused by ischemia. In our preliminary data, histamine was observed to attenuate the up-regulation of autophagy induced by ischemia. But the detailed molecular mechanism is unknown. It is reported that Erk1/2 participates in many pathophysiologic processes regulated by histamine. There are other researches demonstrating that Erk1/2 inhibits autophagy through activating mTOR pathway. Thus we arose the hypothesis that histamine restrains autophagy to protect against myocardial injury through Erk1/2-mTOR pathway. Our project combines cell and animal model experiments to elucidate the function and mechanisms of histamine on autophagy, which could provide new and powerful tactics for the treatment of myocardial infarction.

急性心肌梗死（AMI）是冠脉梗塞引起急性心肌缺血缺氧，导致心肌细胞死亡。对缺血缺氧导致的心肌细胞死亡进行干预是防治心梗发展的关键靶点。在AMI早期，心肌细胞内自噬水平显著上升，自噬过量会导致细胞死亡，但对此过程中调控心肌自噬的因素尚了解甚少。我们前期研究发现，组胺在心梗病人和小鼠模型表达显著上升，内源性组胺缺失促进缺血诱导的心肌细胞死亡。本项目预实验发现组胺能抑制缺血诱导的心肌细胞自噬，具体机制尚不清楚。据报导ERK1/2信号通路参与组胺及其受体介导的多种生理病理功能，另有文献证实ERK1/2通过激活mTOR通路抑制自噬发生。据此我们假设，组胺经ERK1/2~mTOR信号通路抑制缺血缺氧诱导的心肌细胞自噬，对抗心肌损伤。 本项目从细胞分子到整体动物，通过抑制内源组胺表达或注射外源组胺，明确组胺在急性心梗早期对心肌细胞自噬的抑制作用，并揭示其分子机制，为AMI研究和防治提供新思路。

急性心肌梗死（AMI）是冠脉梗塞引起的急性心肌缺血缺氧，导致心肌细胞死亡。对缺血缺氧导致的心肌细胞死亡进行干预是防治心梗发展的关键靶点。组胺是广泛分布的生物胺，参与一系列生物过程的调节。血清组胺水平在急性心肌梗死的早期阶段显着升高，而其作用尚不清楚。在AMI早期，心肌细胞内自噬水平显著上升，自噬过量会导致细胞死亡，但对此过程中调控心肌自噬的因素尚了解甚少。我们研究发现，内源性组胺缺失加重心梗后心肌损伤，伴随着自噬水平的过度激活。体内和体外结果显示通过组胺1型受体，组胺激活ERK1/2通路上调miR-206和miR-216b的表达，miR-206和miR-216b共同作用于靶基因Atg13，抑制缺氧和心梗条件下自噬的过度激活。进一步研究显示Atg13与FADD相互作用促进caspase-8的活化和细胞凋亡。本项目从细胞分子到整体动物，通过抑制内源组胺表达或注射外源组胺，明确组胺在急性心梗早期对心肌保护作用，并揭示了miR-206/216b-Atg13-FADD-caspase8信号通路在自噬和凋亡调控中的互话；研究结果有助于更全面更精准地评估组胺受体拮抗剂的使用，并为心肌梗塞研究和防治提供新思路。