Abstract 5816: The Human Apoa-1 Transgene Suppresses Myeloid Proliferation and Accelerated Atherosclerosis in Ldlr Deficient Mice Reconstituted With ABC Transporter Deficient Bone Marrow
Overexpression or infusions of apoA-1 or HDL lead to reduced atherosclerosis. A major mechanism to explain this effect is thought to be cholesterol efflux from arterial wall macrophage foam cells via ABC transporters. In this study we have tested this hypothesis by transplanting bone marrow deficient in ABCA1 and ABCG1 into atherogenic diet-fed Ldlr deficient mice with or without expression of a human apoA-1 transgene. Unexpectedly, the apoA-1 transgene dramatically suppressed the accelerated atherosclerosis as well as leukocytosis, monocytosis and myeloid cell infiltration of organs in mice receiving double KO bone marrow. Double KO bone marrow showed a 5-fold expansion of hematopoietic stem cells, increased cycling of stem cells, increased myeloid progenitor cells and increased proliferation of bone marrow myeloid cells in response to growth factors. Double KO bone marrow myeloid cells showed increased association of ras with the plasma membrane possibly reflecting increased cholesterol content on the inner leaflet of the plasma membrane and increased ERK signaling in response to IL-3 or GM-CSF treatments. HDL promoted cholesterol efflux and decreased Ras membrane association and ERK signaling and inhibited proliferation of both WT and double KO bone marrow myeloid cells. The findings indicate a novel mechanism in which HDL may suppress atherosclerosis by decreasing myeloid cell proliferation and consequent monocytosis.