20-Hydroxy-5,8,11,14-eicosatetraenoic acid mediates endothelial dysfunction via IκB kinase-dependent endothelial nitric-oxide synthase uncoupling

Jennifer Cheng, Cheng Chia Wu, Katherine H. Gotlinger, Frank Zhang, J R Falck, Dubasi Narsimhaswamy, Michal Laniado-Schwartzman

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Endothelial dysfunction and activation occur in the vasculature and are believed to contribute to the pathogenesis of cardiovascular diseases. We have shown that 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a cytochrome P450 4A-derived eicosanoid that promotes vasoconstriction in the microcirculation, uncouples endothelial nitric-oxide synthase (eNOS) and reduces nitric oxide (NO) levels via the dissociation of the 90-kDa heat shock protein (HSP90) from eNOS. It also causes endothelial activation by stimulating nuclear factor-κB (NF-κB) and increasing levels of proinflammatory cytokines. In this study, we examined signaling mechanisms that may link 20-HETE-induced endothelial dysfunction and activation. Under conditions in which 20-HETE inhibited NO production, it also stimulated inhibitor of NF-κB (IκB) phosphorylation. Both effects were prevented by inhibition of tyrosine kinases and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK). It is noteworthy that inhibitor of IκB kinase (IKK) activity negated the 20-HETE-mediated inhibition of NO production. Immunoprecipitation experiments revealed that treatment of ionophore-stimulated cells with 20-HETE brings about a decrease in HSP90-eNOS association and an increase in HSP90-IKKβ association, suggesting that the activation by 20-HETE of NF-κB is linked to its action on eNOS. Furthermore, addition of inhibitors of tyrosine kinase MAPK and IKK restored the 20-HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries. The results indicate that 20-HETE mediates eNOS uncoupling and endothelial dysfunction via the activation of tyrosine kinase, MAPK, and IKK, and these effects are linked to 20-HETE-mediated endothelial activation.

Original languageEnglish (US)
Pages (from-to)57-65
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number1
DOIs
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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