Involvement of the epidermal growth factor receptor in Pb2+-induced activation of cPLA2/COX-2 genes and PGE2 production in vascular smooth muscle cells

Wei Chiao Chang, Chen Chia Chang, Yung Song Wang, Yu Shiuan Wang, Wei Teng Weng, Tohru Yoshioka, Suh Hang Hank Juo

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Lead (Pb2+) is one of the most common heavy metal pollutants, which can cause chronic cardiovascular diseases. To clarify the mechanism by which Pb2+ induces inflammatory reactions, we examined the expression of inflammatory genes including encoding cyclooxygenase-2 (COX-2), cytosolic phospholipase A2 (cPLA2), and their down stream product prostaglandin E2 (PGE2) in CRL1999 cells that is a vascular smooth muscle cell line from human aorta. The expression of COX-2/cPLA2 genes and PGE2 secretion was increased markedly after cells were exposed to 1μM Pb2+. PD098059, a MEK inhibitor, suppressed Pb2+-mediated inflammatory reactions; this indicates the involvement of the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Furthermore, Pb2+-induced activation of the COX-2/cPLA2 genes was inhibited by both epidermal growth factor receptor (EGFR) inhibitors (AG1478 and PD153035) and EGFR siRNA. Short-term stimulation with Pb2+ induced EGFR phosphorylation at the Tyr residue (position, 1173). Importantly, overexpression of EGFR resulted in a significant potentiation effect on Pb2+-induced gene expression. Taken together, our results indicate that 1μM Pb2+ can induce PGE2 secretion by upregulating the transcription of COX-2/cPLA2 genes. EGFR is the key target in the plasma membrane responsible for transmitting Pb2+ signals in order to trigger downstream inflammatory cascades.

Original languageEnglish
Pages (from-to)45-53
Number of pages9
JournalToxicology
Volume279
Issue number1-3
DOIs
Publication statusPublished - Jan 11 2011
Externally publishedYes

Keywords

  • COX-2
  • CPLA
  • EGFR
  • Lead
  • MAPKs
  • PGE
  • SOC

ASJC Scopus subject areas

  • Toxicology

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