title: Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters.
abstract: The antiatherogenic effect of high-density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) has been largely attributed to their key roles in reverse cholesterol transport (RCT) and cellular cholesterol efflux. Substantial evidence shows that overexpression of human apoA-I reduces atherosclerosis in animal models. However, it is uncertain whether this protection is due to an increase in plasma HDL level or to a local effect in the artery wall. To test the hypothesis that expression of human apoA-I in macrophages can promote RCT in the artery wall, we used a retroviral construct expressing human apoA-I cDNA (MFG-HAI) to transduce ApoE(-/-) bone marrow cells and then transplanted these cells into ApoE(-/-) mice with preexisting atherosclerosis. ApoE(-/-) mice reconstituted with MFG-HAI marrow had a significant reduction (30%) in atherosclerotic lesions in the proximal aorta compared to control mice that received marrow expressing MFG parental virus. Peritoneal macrophages isolated from MFG-HAI mice showed a four- to fivefold increase in mRNA expression levels of both ATP-binding cassette (ABC) A1 and ABCG1 compared to controls. Our data demonstrate that gene transfer-mediated expression of human apoA-I in macrophages can compensate in part for apoE deficiency and delay the progression of atherosclerotic lesions by stimulating ABC-dependent cholesterol efflux and RCT.
authors.affiliation: Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300, USA. yan.ru.su@vanderbilt.edu
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Su
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Amy S
authors.initials: AS
authors.lastname: Major
authors.forename: Dwayne E
authors.initials: DE
authors.lastname: Dove
authors.forename: Wenwu
authors.initials: W
authors.lastname: Zhang
authors.forename: Alyssa H
authors.initials: AH
authors.lastname: Hasty
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000517:prevention & control*; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D015316:Genetic Therapy; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E