β2肾上腺素受体/Gi通路通过抑制β1肾上腺素受体自身抗体生成减轻急性心肌梗死后心脏损伤的作用及机制

急性心梗患者血清中存在高滴度的β1肾上腺素受体（β1-AR）自身抗体（β1-AA），β1-AA可持续激活β1-AR导致心衰，但β1-AA生成及干预机制尚不清楚。自身抗原异常暴露是自身抗体生成的关键机制。前期研究发现心梗患者血清中存在β1-AR细胞外第二环（β1-AR-ECII）肽段；激活β2-AR/Gi通路可减少缺血缺氧心肌细胞上清β1-AR-ECII含量。据此提出假说：自身抗原β1-AR-ECII异常暴露是急性心梗后β1-AA产生及心脏损伤的关键机制；β2-AR/Gi通路通过降低β1-AR-ECII水平从而减少β1-AA生成，保护心脏。本项目拟通过患者、动物、细胞、分子水平，结合质谱、主动免疫等手段，探究急性心梗时β1-AR-ECII异常暴露与β1-AA生成的关系；明确激活β2-AR/Gi通路对抑制心梗后β1-AA生成的作用和机制，从而为改善心梗后β1-AA生成所致心脏损伤提供新的靶点。

There are high titers of β1 adrenergic receptor (β1-AR) autoantibody (β1-AA) in the serum of patients with acute myocardial infarction (AMI). β1-AA can induce continuous activation of β1-AR, resulting in heart failure. However, the generation and intervention mechanism of β1-AA in patients with AMI remain unclear. Abnormal exposure of autoantigens is the key mechanism for autoantibodies production. Our preliminary results showed that β1-AR extracellular second loop (β1-AR-ECII) peptide was present in the serum of patients with myocardial infarction. Moreover, activation of β2 adrenergic receptor (β2-AR) /Gi pathway reduced the level of β1-AR-ECII in the supernatant of cardiomyocytes induced by ischemia and hypoxic. Therefore, we propose the hypothesis that abnormal exposure of autoantigen β1-AR-ECII is the key mechanism for β1-AA production and cardiac injury in post-AMI; β2-AR/Gi can reduce serum level of β1-AR-ECII and β1-AA content to protect from cardiac injury in myocardial infarction. We will clarify the relationship between abnormal exposure to β1-AR-ECII and β1-AA production, and the role and mechanisms of β2-AR/Gi pathway in β1-AA production after AMI from patient, animal, cellular and molecular levels using mass spectrometry, active immunization and ELISA in this research. This study will provide a new therapeutic target to improve the cardiac injury induced by β1-AA after AMI.