Abstract 10754: AMPKγ2 Deficiency Exacerbates Macrophage Recruitment and Inflammation Post-MI via Promoting YY1-CXCL16-CXCR6 Axis

Abstract

Background: Acute myocardial infarction (MI) has got revolutionized therapeutic strategy by applying timely reperfusion therapy in a particular increase of primary percutaneous coronary intervention. Despite this cardiac remodeling following MI are very common with high mortality. A previous study claimed that AMPK played a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. However, whether AMPKγ2 subunit played an important role in MI remains poorly defined. Hypothesis: We assessed the hypothesis that AMPKγ2 played an important role in regulating MI. Methods: AMPKγ2 level in monocytes of myocardial infarction patients was tested by ELISA. Ligation of left anterior descending branch (LAD) surgery was conducted to establish MI model. Lyz2-cre AMPKγ2 and AAV carrying F4/80 promoter for macrophage-specific overexpression AMPKγ2 mice were employed to investigate the role of AMPKγ2 in macrophages derived from MI. Results: AMPKγ2 was relatively highly expressed in the spleen and macrophage. Lyz2-cre AMPKγ2 mice developed worse cardiac dysfunction post-MI by boosting macrophage infiltration and inflammation. Overexpression of AMPKγ2 in macrophages repressed its migration and inflammation and alleviated myocardial injury. Mechanistically, CXCL16-CXCR6 axis was the contributor to macrophage migration, which was alleviated by AMPKγ2 via transcriptional regulation. Further, AMPKγ2 restrained YY1 expression, a key upstream transcription factor of CXCL16, to block the migration of macrophages. AMPKγ2 promoted YY1 degradation via smurf2 mediating ubiquitin-proteasome pathway depending on AMPKα1 subunit-mediating AMPK activity. Therefore, A769662 but not Metformin alleviated AMPKγ2 deficiency-induced migration and inflammation in macrophages. Finally, IFN-γ downregulated HOXA5 to repress AMPKγ2 transcriptional activity. Consistently, AMPKγ2 was dramatically declined in monocytes of MI patients compared to the control group. Conclusion: Macrophage AMPKγ2 deficiency played an important role in cardiac dysfunction following MI by activating the YY1-CXCL16-CXCR6 axis, which can be developed as a precision therapeutic target to ameliorate cardiac remodeling post-MI.