title: Hypoxia-Inducible Factor-1α Expression in Macrophages Promotes Development of Atherosclerosis.
abstract: Atherosclerotic lesions contain hypoxic areas, but the pathophysiological importance of hypoxia is unknown. Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor in cellular responses to hypoxia. We investigated the hypothesis that HIF-1α has effects on macrophage biology that promotes atherogenesis in mice.
  
  
  
  Studies with molecular probes, immunostaining, and laser microdissection of aortas revealed abundant hypoxic, HIF-1α-expressing macrophages in murine atherosclerotic lesions. To investigate the significance of macrophage HIF-1α, Ldlr(-/-) mice were transplanted with bone marrow from mice with HIF-1α deficiency in the myeloid cells or control bone marrow. The HIF-1α deficiency in myeloid cells reduced atherosclerosis in aorta of the Ldlr(-/-) recipient mice by ≈72% (P=0.006).In vitro, HIF-1α-deficient macrophages displayed decreased differentiation to proinflammatory M1 macrophages and reduced expression of inflammatory genes. HIF-1α deficiency also affected glucose uptake, apoptosis, and migratory abilities of the macrophages.
  
  
  
  HIF-1α expression in macrophages affects their intrinsic inflammatory profile and promotes development of atherosclerosis.
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.).
authors.forename: Annemarie
authors.initials: A
authors.lastname: Aarup
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.).
authors.forename: Tanja X
authors.initials: TX
authors.lastname: Pedersen
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.).
authors.forename: Nanna
authors.initials: N
authors.lastname: Junker
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.).
authors.forename: Christina
authors.initials: C
authors.lastname: Christoffersen
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.).
authors.forename: Emil D
authors.initials: ED
authors.lastname: Bartels
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.).
authors.forename: Marie
authors.initials: M
authors.lastname: Madsen
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.).
authors.forename: Carsten H
authors.initials: CH
authors.lastname: Nielsen
authors.affiliation: From the Department of Biomedical Sciences (A.A., T.X.P., N.J., C.C., M.M., C.H.N., L.B.N.) and Department of Clinical Medicine (L.B.N.), University of Copenhagen, Denmark; and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark (C.C., E.D.B., L.B.N.). lars.bo.nielsen@regionh.dk.
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D011973:Receptors, LDL; D002784:Cholesterol; D005947:Glucose
keywords: apoptosis; atherosclerosis; hypoxia; hypoxia-inducible factor 1α; macrophage