title: Apolipoprotein E-/- Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function.
abstract: We previously reported that hemopexin (Hx), a heme scavenger, is significantly increased and associated with proinflammatory high-density lipoprotein under atherogenic conditions. Although it is established that Hx together with macrophages plays a role in mitigating oxidative damage, the role of Hx in the development of atherosclerosis is unknown.
  
  
  
  We used Hx and apoE double-knockout mice (HxE(-/-)) to determine the role of Hx in the development of atherosclerosis. HxE(-/-) mice had significantly more free heme, reactive oxygen species, and proinflammatory high-density lipoprotein in their circulation, when compared with control apoE(-/-) mice. Atherosclerotic plaque area (apoE(-/-)=9.72±2.5×10(4) μm(2) and HxE(-/-)=27.23±3.6×10(4) μm(2)) and macrophage infiltration (apoE(-/-)=38.8±5.8×10(3) μm(2) and HxE(-/-)=103.4±17.8×10(3) μm(2)) in the aortic sinus were significantly higher in the HxE(-/-) mice. Atherosclerotic lesions in the aortas were significantly higher in the HxE(-/-) mice compared with apoE(-/-) mice. Analysis of polarization revealed that macrophages from HxE(-/-) mice were more M1-like. Ex vivo studies demonstrated that HxE(-/-) macrophage cholesterol efflux capacity was significantly reduced when compared with apoE(-/-) mice. Injection of human Hx into HxE(-/-) mice reduced circulating heme levels and human Hx pretreatment of naive bone marrow cells ex vivo resulted in a shift from M1- to M2-like macrophages.
  
  
  
  We conclude that Hx plays a novel protective role in alleviating heme-induced oxidative stress, improving inflammatory properties of high-density lipoprotein, macrophage phenotype and function, and inhibiting the development of atherosclerosis in apoE(-/-) mice.
authors.affiliation: From the Department of Molecular and Medical Pharmacology (N.U.M., S.T.R.) and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (N.U.M., V.G., S.H., A.W., M.N., A.M.F., S.T.R.).
authors.forename: Niyati U
authors.initials: NU
authors.lastname: Mehta
authors.affiliation: From the Department of Molecular and Medical Pharmacology (N.U.M., S.T.R.) and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (N.U.M., V.G., S.H., A.W., M.N., A.M.F., S.T.R.).
authors.forename: Victor
authors.initials: V
authors.lastname: Grijalva
authors.affiliation: From the Department of Molecular and Medical Pharmacology (N.U.M., S.T.R.) and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (N.U.M., V.G., S.H., A.W., M.N., A.M.F., S.T.R.).
authors.forename: Susan
authors.initials: S
authors.lastname: Hama
authors.affiliation: From the Department of Molecular and Medical Pharmacology (N.U.M., S.T.R.) and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (N.U.M., V.G., S.H., A.W., M.N., A.M.F., S.T.R.).
authors.forename: Alan
authors.initials: A
authors.lastname: Wagner
authors.affiliation: From the Department of Molecular and Medical Pharmacology (N.U.M., S.T.R.) and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (N.U.M., V.G., S.H., A.W., M.N., A.M.F., S.T.R.).
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.affiliation: From the Department of Molecular and Medical Pharmacology (N.U.M., S.T.R.) and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (N.U.M., V.G., S.H., A.W., M.N., A.M.F., S.T.R.).
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.affiliation: From the Department of Molecular and Medical Pharmacology (N.U.M., S.T.R.) and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (N.U.M., V.G., S.H., A.W., M.N., A.M.F., S.T.R.). sreddy@mednet.ucla.edu.
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006418:Heme / Q000378:metabolism; D006466:Hemopexin / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D017382:Reactive Oxygen Species / Q000097:blood; D015398:Signal Transduction
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D002784:Cholesterol; D006418:Heme; D006466:Hemopexin; D018836:Inflammation Mediators; D008075:Lipoproteins, HDL; D017382:Reactive Oxygen Species; C577833:Abca1 protein, mouse
keywords: cholesterol; heme; inflammation; macrophages; monocytes