Native LDL induces interleukin-8 expression via H2O 2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells

Sung Woo Ryoo, Dong Uk Kim, Misun Won, Kyung Sook Chung, Young Joo Jang, Goo Taek Oh, Song Kyu Park, Pil Jae Maeng, Hyang Sook Yoo, Kwang Lae Hoe

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Background and objectives: 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. Methods and 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)-κB, 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 H2O 2, the phosphorylation of p38 MAPK, the activation of AP-1, and the participation of NF-κB.

Original languageEnglish
Pages (from-to)185-193
Number of pages9
JournalCardiovascular Research
Volume62
Issue number1
DOIs
StatePublished - 1 Apr 2004

Keywords

  • Atherosclerosis
  • Interleukins
  • Lipoproteins
  • MAP kinase
  • Smooth muscle

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