ABCA7: Cellular Functions and Role in Atherosclerosis

ABCA7 and ABCA1 are related ABC transporters that have been proposed to function in cellular lipid efflux and in phagocytosis of apoptotic cells. When overexpressed in 293 cells, ABCA7 is present in the cell surface, binds apoA-l and promotes phospholipid but not cholesterol efflux to apoA-l. In resting macrophages ABCA7 is found intracellularly and does not contribute to lipid efflux. During phagocytosis of apoptotic cells, macrophage ABCA7 localizes to phagocytic cups and phagosomes. Genetic knock-down of ABCA7 (siRNA or knock-out mouse cells) markedly reduces macrophage phagocytosis of apoptotic cells but does not affect Fc receptor-mediated phagocytosis. The central hypothesis is that ABCA7 has an essential role in macrophage phagocytosis of apoptotic cells and thus may influence inflammatory processes such as atherosclerosis. The specific aims are 1) To define the cellular mechanisms underlying the involvement of ABCA7 in phagocytosis of apoptotic cells;2) To evaluate cellular functions of ABCA7 relevant to atherogenesis, such as phagocytic uptake of different forms of LDL promoting foam cell formation, and possible interactions of ABCA7 with LRP that result in altered signaling via MAP kinase pathways and increased MCP-1 release;and 3) To use ABCA7 deficient mice to evaluate effects of ABCA7 expression on atherogenesis in apoE-/- or LDLR-/- backgrounds. Our hypothesis is that a defect in clearance of apoptotic cells in atherosclerotic lesions will lead to accumulation of apoptotic cells, increased lesional necrotic core formation and increased inflammatory features of lesions. Defective apoptotic cell removal may also lead to features of auto-immunity. Overall, this proposal will elucidate the in vivo functions of a novel ABC transporter and its role in macrophage clearance of apoptotic cells, inflammation and atherogenesis.