Cholesterol efflux: a novel regulator of myelopoiesis and atherogenesis.
Monocytosis and neutrophilia are well-established risk factors for atherosclerosis and seem to play a causative role in lesion development. Studies in mice with defects in cholesterol efflux pathways have identified novel roles for the ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and apolipoprotein E in suppressing hematopoietic stem cell proliferation, mobilization, and the production of monocytes and neutrophils in the bone marrow. In addition, stem cell mobilization to the spleen initiates extramedullary hematopoiesis, which acts as a monocytic reservoir. Increased monocyte and neutrophil levels drive atherogenesis and its complications. Increasing high-density lipoprotein levels and cholesterol efflux can reverse excessive myelopoiesis and stem cell mobilization, suggesting a novel antiatherogenic effect of some forms of high-density lipoprotein elevation. After a myocardial infarction, splenic Ly-6C(hi) monocyte populations are sustained by a second wave of stem cell mobilization from the bone marrow and continue to enter atheroma, accelerating atherogenesis. Because activation of cholesterol efflux pathways can inhibit stem cell proliferation, mobilization, and monocyte production, this may provide a rationale for boosting high-density lipoprotein levels after a myocardial infarction to prevent reocclusion.
Department of Medicine, Columbia University, 630W 168th St, College of Physicians and Surgeons 8-401, New York, NY 10032, USA.
Alan R
AR
Tall
Laurent
L
Yvan-Charvet
Marit
M
Westerterp
Andrew J
AJ
Murphy
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D002465:Cell Movement; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D025461:Feedback, Physiological; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D038042:Myelopoiesis; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors
D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D002784:Cholesterol