Abstract
Abstract 4797
Atherosclerotic cardiovascular disease is associated with leukocytosis. Hypercholesterolemic animal models like apolipoprotein E deficient (Apoe-/-) mice develop leukocytosis and monocytosis. However, the mechanisms linking hypercholesterolemia to leukocytosis are poorly understood. Recent studies in our laboratory have shown increased proliferation of hematopoietic stem and progenitor cells (HSPCs) and leukocytosis in mice deficient in efflux of cholesterol to HDL. Apoe also appears to be highly expressed in HSPCs, suggesting a role in cholesterol efflux. We hypothesized that leukocytosis in Apoe-/- mice might be associated with increased proliferation and expansion of HSPCs and that lowering their cholesterol levels with atorvastatin would suppress this expansion. Wild type (WT), LDL receptor-deficient (Ldlr-/-), and Apoe-/- mice were fed a Western-type diet (WTD) for 0, 10 and 20 weeks (8 mice per group per timepoint). After 10 weeks of WTD, 8 Apoe-/- received WTD with atorvastatin (0.01% wt/wt) for the remainder of the study. On chow diet Apoe-/- mice had monocytosis (+66% vs WT, P<.01), neutrophilia (+90%, P<.0001), and expanded HSPCs (+46% compared to the other groups, P<.05). After 10 weeks of WTD, leukocytosis developed further in Apoe-/- mice, along with increased bone marrow proliferation (+86%, P<.01) and more granulocyte-macrophage (GM)-colony formation (110% more, P<.01). After 20 weeks, all mice had developed monocytosis, neutrophilia, and expansion of the HSPCs compared to their chow starting point. Atorvastain reduced plasma cholesterol by 60% (P<.01) and attenuated monocytosis (30% reduction, P<.05) and neutrophilia (35% reduction, P<.05), but did not reduce the HSPCs levels in Apoe-/- mice. In conclusion, leukocytosis and expansion of HSPCs in Apoe-/- mice is observed on a chow diet and develops earlier than in the other models on the WTD, consistent with a role of APOE in modulating HSPCs cholesterol content. However, dietary hypercholesterolemia eventually led to HSPCs expansion paralleling leukocytosis in all groups, suggesting this is a general response to dietary hypercholesterolemia. Leukocytosis was attenuated with atorvastatin treatment through a mechanism unrelated to the reversal of HSPCs expansion.
Tall: CSL: Consultancy; Merck: Consultancy; Roche: Consultancy; Arisaph: Consultancy.
Author notes
Asterisk with author names denotes non-ASH members.