title: ApoE regulates hematopoietic  stem cell proliferation, monocytosis,  and monocyte accumulation  in atherosclerotic lesions in mice.
abstract: Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe⁻/⁻ mice fed a chow or Western- type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1⁻/⁻ mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1- and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe⁻/⁻ mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA. am3440@columbia.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Mani
authors.initials: M
authors.lastname: Akhtari
authors.forename: Sonia
authors.initials: S
authors.lastname: Tolani
authors.forename: Tamara
authors.initials: T
authors.lastname: Pagler
authors.forename: Nora
authors.initials: N
authors.lastname: Bijl
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Kuo
authors.forename: Mi
authors.initials: M
authors.lastname: Wang
authors.forename: Marie
authors.initials: M
authors.lastname: Sanson
authors.forename: Sandra
authors.initials: S
authors.lastname: Abramowicz
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Bochem
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: Laurent
authors.initials: L
authors.lastname: Yvan-Charvet
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050197:Atherosclerosis / Q000473:pathology* / Q000503:physiopathology*; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000502:physiology*; D006801:Humans; D007964:Leukocytosis / Q000473:pathology / Q000503:physiopathology; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009000:Monocytes / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008074:Lipoproteins; D011509:Proteoglycans; D011973:Receptors, LDL; D002784:Cholesterol