title: Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL.
abstract: Tissue cholesterol accumulation, macrophage infiltration, and inflammation are features of atherosclerosis and some forms of dermatitis. HDL and its main protein, apoAI, are acceptors of excess cholesterol from macrophages; this process inhibits tissue inflammation. Recent epidemiologic and clinical trial evidence questions the role of HDL and its manipulation in cardiovascular disease. We investigated the effect of ectopic macrophage apoAI expression on atherosclerosis and dermatitis induced by the combination of hypercholesterolemia and absence of HDL in mice. Hematopoietic progenitor cells were transduced to express human apoAI and transplanted into lethally irradiated LDL receptor(-/-)/apoAI(-/-) mice, which were then placed on a high-fat diet for 16 weeks. Macrophage apoAI expression reduced aortic CD4(+) T-cell levels (-39.8%), lesion size (-25%), and necrotic core area (-31.6%), without affecting serum HDL or aortic macrophage levels. Macrophage apoAI reduced skin cholesterol by 39.8%, restored skin morphology, and reduced skin CD4(+) T-cell levels. Macrophage apoAI also reduced CD4(+) T-cell levels (-32.9%) in skin-draining lymph nodes but had no effect on other T cells, B cells, dendritic cells, or macrophages compared with control transplanted mice. Thus, macrophage apoAI expression protects against atherosclerosis and dermatitis by reducing cholesterol accumulation and regulating CD4(+) T-cell levels, without affecting serum HDL or tissue macrophage levels.
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR. Electronic address: tavori@ohsu.edu.
authors.forename: Hagai
authors.initials: H
authors.lastname: Tavori
authors.affiliation: Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Su
authors.affiliation: Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Yancey
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giunzioni
authors.affiliation: Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Wilhelm
authors.affiliation: Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: John L
authors.initials: JL
authors.lastname: Blakemore
authors.affiliation: Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Manal
authors.initials: M
authors.lastname: Zabalawi
authors.affiliation: Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.affiliation: Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D003872:Dermatitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL
keywords: apolipoprotein AI; bone marrow transplant; gene therapy; hematopoietic progenitor cells; high density lipoprotein