Abstract 17333: Myeloid-Specific Deletion of Epsins 1 and 2 Reduces Atherosclerosis by Preventing LRP-1 Downregulation

Abstract

Introduction: Atherosclerosis is in part caused by immune and inflammatory cell infiltration into the vascular wall, leading to enhanced inflammation and lipid accumulation in the aortic endothelium. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution lesion macrophages make to fuel atherosclerosis, whether and how myeloid specific epsins promote atherogenesis is an open and significant question. Hypothesis: We hypothesize that myeloid specific epsins regulate lesion macrophage function during atherosclerosis. Methods and Results: We engineered myeloid cell-specific epsins double knockout mice (LysM-DKO)on an ApoE -/- background. On Western diet, these mice exhibited marked decrease in atherosclerotic lesion formation, diminished immune and inflammatory cell content in aortas, and reduced necrotic core content but increased smooth muscle cell content in aortic root sections.Epsins deficiency hindered foam cell formation and suppressed the pro-inflammatory macrophage phenotype but increased efferocytosis and the anti-inflammatory macrophage phenotype in primary macrophages.Mechanistically, we show that epsins loss specifically increased total and surface levels of LRP-1, an efferocytosis receptor with anti-atherosclerotic properties. We further show thatepsin and LRP-1 interact via epsin’s Ubiquitin Interacting Motif (UIM) domain. Oxidized LDL treatment increased LRP-1 ubiquitination and subsequent binding to epsin while mutation of cytoplasmic lysine residues attenuated LRP-1 ubiquitination, suggesting that epsins promote the ubiquitin-dependent internalization and downregulation of LRP-1. Crossing ApoE -/- /LysM-DKO mice onto a LRP-1 heterozygous background restored, in part, atherosclerosis, suggesting that epsin-mediated LRP-1 downregulation in macrophages plays a pivotal role in propelling atherogenesis. Conclusions: Myeloid epsins promote atherogenesis by facilitating pro-inflammatory macrophage recruitment and inhibiting efferocytosis in part by downregulating LRP-1, implicating that targeting epsins in macrophages may serve as a novel therapeutic strategy to treat atherosclerosis. Key words: epsin, macrophage, atherosclerosis, LRP-1, inflammation, efferocytosis