20-Hydroxyeicosatetraenoic acid stimulates nuclear factor-κB activation and the production of inflammatory cytokines in human endothelial cells

Tsuneo Ishizuka, Jennifer Cheng, Harpreet Singh, Marco D. Vitto, Vijay L. Manthati, J R Falck, Michal Laniado-Schwartzman

Research output: Contribution to journalArticle

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Abstract

Endothelial dysfunction is associated with endothelial cell activation, i.e., up-regulation of surface cell adhesion molecules and the release of proinflammatory cytokines. 20-Hydroxyeicosatetraenoic acid (HETE), a major vasoactive eicosanoid in the microcirculation, has been implicated in the regulation of endothelial cell function through its angiogenic and pro-oxidative properties. We examined the effects of 20-HETE on endothelial cell activation in vitro. Cells transduced with adenovirus containing either CYP4A1 or CYP4A2 produced higher levels of 20-HETE, and they demonstrated increased expression levels of the adhesion molecule intercellular adhesion molecule (ICAM) (4-7-fold) and the oxidative stress marker 3-nitrotyrosine (2-3-fold) compared with cells transduced with control adenovirus. Treatment of cells with 20-HETE markedly increased levels of prostaglandin (PG) E2 and 8-epi-isoprostane PGF, commonly used markers of activation and oxidative stress, and most prominently, interleukin-8, a potent neutrophil chemotactic factor whose overproduction by the endothelium is a key feature of vascular injury. 20-HETE at nanomolar concentrations increased inhibitor of nuclear factor-κB phosphorylation by 2 to 5-fold within 5 min, which was followed with increased nuclear translocation of nuclear factor-κB (NF-κB). Likewise, 20-HETE activated the mitogen-activated protein kinase/ extracellular signal-regulated kinase (MAPK/ERK) pathway by stimulating phosphorylation of ERK1/2. Inhibition of NF-κB activation and inhibition of ERK1/2 phosphorylation inhibited 20-HETE-induced ICAM expression. It seems that 20-HETE triggers NF-κB and MAPK/ERK activation and that both signaling pathways participate in the cellular mechanisms by which 20-HETE activates vascular endothelial cells.

Original languageEnglish (US)
Pages (from-to)103-110
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume324
Issue number1
DOIs
StatePublished - Jan 1 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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