title: Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells.
abstract: OBJECTIVE
  Endothelial and monocytic cells appear to play a key role in the initiation and progression of atherosclerosis and restenosis via the upregulation of inflammatory cytokines and the formation of oxidized low-density lipoprotein (ox-LDL). However, the role of smooth muscle cells (SMCs) has been underestimated and is not well understood. It was investigated for the first time that native LDL stimulates human SMCs to secrete IL-8. The aim of this study was to investigate the signaling pathway involved in the upregulation of IL-8, induced by LDL in human aortic SMCs.
  
  
  RESULTS
  LDL-induced IL-8 expression (mRNA and protein) is specific to SMCs and likely to be regulated at the transcription level in dose- and time-dependent manners, as judged by experiments with actinomycin D and ELISA. Although both p38 and ERK 1/2 MAPKs were activated by LDL, only p38 MAPK is responsible for the LDL effects, as evidenced by a complete blockade of IL-8 upregulation by SB203580. Pretreatment with catalase significantly decreased the extent of IL-8 upregulation, indicating that H2O2 is necessary for the LDL response. Activation of activator protein (AP)-1, but not nuclear factor (NF)-kappaB, by p38 or H2O2 appears to be necessary along with the concomitant upregulation of c-fos and c-JUN, as judged by electrophoretic mobility shift and luciferase reporter assays.
  
  
  CONCLUSIONS
  These data demonstrated that LDL stimulates SMCs to induce IL-8 production in dose- and time-dependent manners at the transcription level and that the LDL signaling in hAoSMCs is conveyed via the generation of H2O2, the phosphorylation of p38 MAPK, the activation of AP-1, and the participation of NF-kappaB.
authors.affiliation: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yusong, Daejeon, South Korea.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Ryoo
authors.forename: Dong-Uk
authors.initials: DU
authors.lastname: Kim
authors.forename: Misun
authors.initials: M
authors.lastname: Won
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Jang
authors.forename: Goo-Taek
authors.initials: GT
authors.lastname: Oh
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Pil-Jae
authors.initials: PJ
authors.lastname: Maeng
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Yoo
authors.forename: Kwang-Lae
authors.initials: KL
authors.lastname: Hoe
mesh_terms: D001011:Aorta; D002109:Caffeic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D003331:Coronary Vessels; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002109:Caffeic Acids; D005419:Flavonoids; D007093:Imidazoles; D016209:Interleukin-8; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D011725:Pyridines; D012717:Sesquiterpenes; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; C002669:parthenolide; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one