Abstract 423: Role of Autophagy in Macrophages During Acute Myocardial Infraction

Abstract

Acute myocardial infarction (AMI) is associated with inflammation and proinflammatory cytokine release, including IL-1β, but the role of NLRP3 inflammasome in cardiac injury remains controversial and requires further investigation. Autophagy, important for stress responses in injury and diseases, is a self-digestion process for the recycling of cytosolic macromolecules and damaged organelles. While autophagy has been previously investigated in cardiac muscle cells in AMI, its role in inflammatory cells is unknown. We generated macrophage (Mφ)-specific Atg16L1 KO mice ( Atg16l1 fl/fl LysM-Cre) and performed permanent ligation of the left anterior descending artery (LAD) using closed-chest model. 24 hours post ligation, Mφ-specific Atg16L1 KO mice had significantly larger infarction area as measured by myoglobin staining, and more TUNEL staining compared with control groups. This suggested that autophagy in macrophages plays a cardioprotective role during AMI. Since autophagy negatively regulates NLRP3 inflammasome activation and IL-1β secretion, we investigated the role of NLRP3 inflammasome in AMI. NLRP3 KO mice were subjected to LAD ligation and KO mice had less infarction compared with control mice. We also observed reduced infarction in IL-1R1 deficient mice, suggesting that NLRP3 inflammasome and subsequent IL-1β secretion and signaling play a role in AMI pathology. Multiple reports indicate that autophagy associated proteins induction have reduced expression in aged tissues and that autophagy diminishes with aging. We therefore investigated IL-1 signaling blockade with Anakinra (IL-1 receptor antagonist) in aged C57BL/6 mice. Mice were injected with Anakinra daily 10 mg/kg starting 1 h after LAD ligation. While we observed 14% larger infarct size in aged mice (18 months) compared to young mice (12 weeks), Anakinra treatment displayed significantly reduced infarction compared with age matched controls and the reduction of infarction by anakinra treatment was significantly greater in aged mice (75% reduction) compared with young mice (50% reduction). Taken together, these data demonstrate that autophagy plays a protective role in macrophages and NLRP3 and IL-1β mediate pathology, with an increased effect on aged mice during AMI.