Abstract 19263: Enhancing Cholesterol Efflux Pathways Suppresses Hematopoietic Stem Cell Proliferation and Monocytosis in apoE−/− Mice
Atherosclerosis is associated with monocytosis and attenuating monocytosis results in a reduction in atherosclerosis. Mice deficient in ABCA1 and ABCG1 have leukocytosis and monocytosis that is reversed by Increased HDL levels (human apoA-I transgene) which promotes cholesterol efflux and reduces the proliferation of hematopoietic stem and progenitor cells (HSPCs). Apoe−/− mice also have monocytosis that is associated with expansion of the HSPC population. We hypothesized that promotion of cholesterol efflux from HSPCs in WTD-fed apoE−/− mice, by infusion of rHDL or treatment with LXR activators to up-regulate ABCA1/G1 would suppress HSPC proliferation and monocytosis. A dose response study (40, 80, 120mg/kg) revealed that rHDL (CSL-111) suppressed leukocytosis, monocytosis and proliferation of HSPCs with maximum effect at 80mg/kg, similar to doses previously shown to be effective in human IVUS studies. Treatment with LXR activator (20mg/kg X 3) also resulted in decreased leukocytosis, monocytosis and HSPC proliferation, and administration of rHDL+LXR activator produced larger reductions in these parameters than either treatment alone. Interestingly, circulating cells were only slightly reduced (to pre-WTD levels) in WT mice, with no changes observed in HSPCs. As IL-3 drives proliferation of HSPCs we examined the IL-3 common β-subunit (IL-3βR) expression in HSPCs. We discovered that apoE−/− mice have an increased population of IL-3βR+ HSCs compared to WT mice (apoE−/−:9.6% vs WT:5.4% P<0.01). IL-3βR+ HSPCs were significantly reduced by rHDL+LXR (Saline:9.6% vs rHDL+LXR:6.25% P<0.05) to WT levels, while the latter were not significantly changed. In conclusion, stimulation of cholesterol efflux from HSPCs by rHDL infusion and LXR activator treatment leads to reduced cell surface expression of the IL-3βR, decreased proliferation of HPSCs and reduced leukocytosis and monocytosis. These treatments were without effect in WT mice suggesting that they activate a homeostatic mechanism returning HSPC proliferation to normal under hypercholesterolemic conditions.
- © 2010 by American Heart Association, Inc.