title: Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Endothelial Cells Accelerates Atherosclerosis in Mice.
abstract: Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1.
  
  
  
  Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding Abca1(fl/fl)Abcg1(fl/fl)Ldlr(-/-) mice with the Tie2Cre strain, followed by irradiation and transplantation of Abca1(fl/fl)Abcg1(fl/fl) bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-type diet, both single EC-Abca1 and Abcg1 deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-Abca1/g1 deficiency caused a significant further increase in lesion area at both sites. EC-Abca1/g1 deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque. Abca1/g1 deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by ABCG1 deficiency in human aortic ECs.
  
  
  
  These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow.
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.). mw2537@columbia.edu.
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Ian W
authors.initials: IW
authors.lastname: Tattersall
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Fotakis
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Bochem
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Molusky
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Vusisizwe
authors.initials: V
authors.lastname: Ntonga
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Abramowicz
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Welch
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.affiliation: From the Division of Molecular Medicine, Department of Medicine (M.W., P.F., A.E.B., M.M.M., V.N., S.A., C.L.W., A.R.T.), Naomi Berrie Diabetes Center (K.T., D.A.), and Department of Pathology, Obstetrics, and Gynaecology (I.W.T., J.K.), Columbia University, New York, NY; Section on Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands (M.W.); Department of Diabetes, Endocrinology, and Metabolism, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan (K.T.); and Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000172:deficiency* / Q000235:genetics; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012039:Regional Blood Flow; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques; D014916:Whole-Body Irradiation
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D002784:Cholesterol; D018836:Inflammation Mediators; D052250:Nitric Oxide Synthase Type III; D011973:Receptors, LDL; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C496315:Nos3 protein, mouse
keywords: ATP-binding cassette transporters; atherosclerosis; endothelium; hypercholesterolemia