title: Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes.
abstract: OBJECTIVE
  Although the role of monocytes in the pathogenesis of atherosclerosis is well established, the persistent vascular inflammation remains largely unexplained. Recently, our group reported that stimulation of monocytes with various microbial products can induce a long-lasting proinflammatory phenotype via epigenetic reprogramming, a process termed trained immunity. We now hypothesize that oxidized low-density lipoprotein (oxLDL) also induces a long-lasting proinflammatory phenotype in monocytes, which accelerates atherosclerosis by proinflammatory cytokine production and foam cell formation.
  
  
  RESULTS
  Isolated human monocytes were exposed for 24 hours to medium or oxLDL. After washing and resting for 6 days, the cells were exposed to toll-like receptor 2 and 4 agonists. Pre-exposure to oxLDL increased mRNA expression and protein formation on toll-like receptor 2 and 4 stimulation of several proatherogenic proteins, including interleukin-6, interleukin-18, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein 1, and matrix metalloproteinase 2 and 9. In addition, foam cell formation was enhanced after oxLDL exposure, which was associated with an upregulation of scavenger receptors CD36 and scavenger receptor-A and downregulation of ATP-binding cassette transporters, ABCA1 and ABCG1. Chromatin immunoprecipitation performed 6 days after oxLDL stimulation demonstrated increased trimethylation of lysine 4 at histone 3 in promoter regions of tnfα, il-6, il-18, mcp-1, mmp2, mmp9, cd36, and sr-a. Finally, pretreatment of the monocytes with the histone methyltransferase inhibitor methylthioadenosine completely prevented the oxLDL-induced long-lasting proinflammatory phenotype.
  
  
  CONCLUSIONS
  Brief exposure of monocytes to a low concentration of oxLDL induces a long-lasting proatherogenic macrophage phenotype via epigenetic histone modifications, characterized by increased proinflammatory cytokine production and foam cell formation.
authors.affiliation: From the Department of Internal Medicine, Division of Experimental Medicine (S.B., J.Q., L.A.B.J., J.W.M.v.d.M., M.G.N.), and Division of Vascular Medicine (N.P.R.), and the Department of Pharmacology-Toxicology (N.P.R.), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Siroon
authors.initials: S
authors.lastname: Bekkering
authors.affiliation: From the Department of Internal Medicine, Division of Experimental Medicine (S.B., J.Q., L.A.B.J., J.W.M.v.d.M., M.G.N.), and Division of Vascular Medicine (N.P.R.), and the Department of Pharmacology-Toxicology (N.P.R.), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Quintin
authors.affiliation: From the Department of Internal Medicine, Division of Experimental Medicine (S.B., J.Q., L.A.B.J., J.W.M.v.d.M., M.G.N.), and Division of Vascular Medicine (N.P.R.), and the Department of Pharmacology-Toxicology (N.P.R.), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: From the Department of Internal Medicine, Division of Experimental Medicine (S.B., J.Q., L.A.B.J., J.W.M.v.d.M., M.G.N.), and Division of Vascular Medicine (N.P.R.), and the Department of Pharmacology-Toxicology (N.P.R.), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: From the Department of Internal Medicine, Division of Experimental Medicine (S.B., J.Q., L.A.B.J., J.W.M.v.d.M., M.G.N.), and Division of Vascular Medicine (N.P.R.), and the Department of Pharmacology-Toxicology (N.P.R.), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: From the Department of Internal Medicine, Division of Experimental Medicine (S.B., J.Q., L.A.B.J., J.W.M.v.d.M., M.G.N.), and Division of Vascular Medicine (N.P.R.), and the Department of Pharmacology-Toxicology (N.P.R.), Radboud University Medical Center, Nijmegen, The Netherlands. Niels.Riksen@Radboudumc.nl.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005487:Foam Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D016207:Cytokines; D004791:Enzyme Inhibitors; D006657:Histones; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: atherosclerosis; epigenomics; inflammation; monocytes; oxidized low-density lipoprotein