title: Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.
abstract: Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1(-/-)) or apoE from macrophages.
  
  
  
  Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, MΦLRP1(-/-), apoE(-/-) or apoE(-/-)/MΦLRP1(-/-)(DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C(hi) monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR(-/-) and apoE(-/-)→LDLR(-/-) mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C(hi) monocyte levels in MΦLRP1(-/-)→LDLR(-/-) and DKO→LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression.
  
  
  
  Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giunzioni
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Hagai
authors.initials: H
authors.lastname: Tavori
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Roman
authors.initials: R
authors.lastname: Covarrubias
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Youmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Ormseth
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: Amy S
authors.initials: AS
authors.lastname: Major
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: John M
authors.initials: JM
authors.lastname: Stafford
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.).
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.affiliation: From the Division of Cardiovascular Medicine (L.Z., R.C., L.D., Y.Z., A.S.M., M.F.L.), Division of Diabetes, Endocrinology, and Metabolism (L.Z., J.M.S.), Division of Rheumatology, Department of Medicine (M.O.), Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Healthcare System, Nashville (L.Z., J.M.S.); and Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland (I.G., H.T., S.F.). fazio@ohsu.edu.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000068879:Adalimumab / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000950:Antigens, Ly / Q000378:metabolism; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation
chemical_list: D000893:Anti-Inflammatory Agents; D000950:Antigens, Ly; D001057:Apolipoproteins E; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; C494192:Ly-6C antigen, mouse; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000068879:Adalimumab
keywords: atherosclerosis; inflammation; low density lipoprotein receptor-related protein-1; macrophages; tumor necrosis factor-alpha