RGD Reference Report - 20-hydroxy-5,8,11,14-eicosatetraenoic acid mediates endothelial dysfunction via IkappaB kinase-dependent endothelial nitric-oxide synthase uncoupling. - Rat Genome Database

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20-hydroxy-5,8,11,14-eicosatetraenoic acid mediates endothelial dysfunction via IkappaB kinase-dependent endothelial nitric-oxide synthase uncoupling.

Authors: Cheng, J  Wu, CC  Gotlinger, KH  Zhang, F  Falck, JR  Narsimhaswamy, D  Schwartzman, ML 
Citation: Cheng J, etal., J Pharmacol Exp Ther. 2010 Jan;332(1):57-65. doi: 10.1124/jpet.109.159863. Epub 2009 Oct 19.
RGD ID: 7495776
Pubmed: PMID:19841472   (View Abstract at PubMed)
PMCID: PMC2802478   (View Article at PubMed Central)
DOI: DOI:10.1124/jpet.109.159863   (Journal Full-text)

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-kappaB (NF-kappaB) and increasing levels of pro-inflammatory 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-kappaB (IkappaB) 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 IkappaB 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-IKKbeta association, suggesting that the activation by 20-HETE of NF-kappaB 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.

Objects referenced in this article
Gene Ikbkb inhibitor of nuclear factor kappa B kinase subunit beta Rattus norvegicus

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