HDL and ABC Transporters Reduce the Proliferation of Hematopoietic Stem and Progenitor Cells, with Anti-atherogenic Consequences
Leukocytosis is a risk factor for athero-thrombotic disease in humans, and develops in animal models of atherosclerosis in response to feeding high fat, high cholesterol diets. The ATP binding cassette transporters ABCA1 and ABCG1 promote cholesterol efflux to apoA-1 and HDL, respectively and are targets of LXR transcription factors. Mice lacking ABCA1/G1 develop a dramatic myeloproliferative phenotype with monocytosis and neutrophilia, associated with expansion and proliferation of hematopoietic stem and myeloid progenitor populations (HSPCs). The transporters are highly expressed in HSPCs where they act to control proliferative responses to growth factors (IL-3, GM-CSF) by regulating plasma membrane lipid rafts and cell surface expression of the common beta subunit of the IL-3/GM-CSF receptor. In Western type diet fed Apoe-/- mice, monocytosis and neutrophilia also develop in association with proliferation and expansion of hematopoietic stem, multipotential progenitor and myeloid progenitor cell populations in the bone marrow and spleen. Apoe is highly expressed in long term hematopoietic stem cells and to a lesser extent in progenitor populations, and acts in a cell autonomous fashion to control myeloid proliferation, monocytosis and accumulation of monocytes in atherosclerotic lesions. Treatment of Apoe-/- mice with infusions of reconstituted HDL and/or LXR activator resulted in normalization of HSPC proliferation, monocytosis and neutrophilia. Together, the findings suggest that ApoE acts in concert with the ATP binding cassette transporters ABCA1 and ABCG1 to control HSPC and myeloid proliferation, monocytosis and atherogenesis. LXR activators and rHDL infusions exert anti-atherogenic effects by controlling HSPC and myeloid proliferation.
- © 2011 by American Heart Association, Inc.