Abstract 506: Targeting Macrophage Epsins Inhibits Lipid Uptake And Facilitates Cholesterol Efflux In Atherosclerosis

Abstract

Resolving atheroma and hindering their transition to vulnerable atherosclerotic plaque is pivotal in preventing deadly episodes such as heart attacks and strokes. Despite recent advances in the treatment, atherosclerosis remains the root cause of death worldwide. Excess cholesterol accumulation and deposition trigger a complex inflammatory response in atherosclerosis. Our recent studies demonstrate that epsins, a family of endocytic adaptors, are critically responsible for the aforesaid events in atherosclerosis; however, the underlying mechanisms and whether targeting epsins hinders cholesterol uptake, promote cholesterol efflux and reverse transport in macrophages to reduce inflammation and accelerate atheroma resolution remains an open question. To explore the therapeutic intervention by harnessing recent development in nanomedicine, we silenced epsins in lesional macrophages by specific delivery of nanoparticles (NPs) carrying epsin siRNAs. We showed that inhibit epsins significantly diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, epsins bind to CD36 to facilitate CD36-mediated lipid uptake by enhancing its endocytosis and recycling. Conversely, epsins promote ABCG1 degradation via lysosomes and hamper ABCG1-mediated cholesterol efflux and reverse cholesterol transport. Furthermore, myeloid-specific epsins double knockout mice (LysM-DKO) harboring a genetically reduced ABCG1 level (LysM-DKO-ABCG1 fl/+ ) were generated. In LysM-DKO-ABCG1 fl/+ macrophages, enhanced cholesterol efflux and reverse transport due to epsins deficiency was suppressed. Our findings suggest that targeting epsins in lesional macrophages may offer therapeutic benefits in preventing or treating advanced atherosclerosis.