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Mechanisms of vascular dysfunction in COPD and effects of a novel soluble epoxide hydrolase inhibitor in smokers

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  • Lucy Yang
  • Joseph Cheriyan
  • David D Gutterman
  • Ruth J Mayer
  • Zsuzsanna Ament
  • Jules L Griffin
  • Aili L Lazaar
  • David E Newby
  • Ruth Tal-Singer
  • Ian B Wilkinson

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    Rights statement: Open Access funded by Wellcome Trust Under a Creative Commons license

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    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
JournalChest
Early online date21 Nov 2016
DOIs
Publication statusE-pub ahead of print - 21 Nov 2016

Abstract

BACKGROUND: Smoking and chronic obstructive pulmonary disease (COPD) are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD, and a novel sEH inhibitor GSK2256294 attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo.

METHODS: Endogenous and stimulated endothelial release of EETs was assessed in 12 COPD patients, 11 overweight smokers, and 2 matched control groups, using forearm plethysmography with intra-arterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilatation in human resistance arteries were assessed in vitro and in vivo in a Phase 1 clinical trial in healthy overweight smokers.

RESULTS: Compared to controls, there was reduced vasodilatation to bradykinin (p=0.005), blunted effect of fluconazole on bradykinin-induced vasodilatation (p=0.03), and a trend towards reduced basal EET/DHETs ratio in COPD patients (p=0.08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilatation compared to vehicle (90±4.2% vs. 72.6±6.2% maximal dilatation), and shifted the bradykinin EC50 (-8.33±0.172 vs. -8.10±0.118 logM; p=0.001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338±46% pre-dose to 566±110% post single dose (p=0.02), and to 503±123% post chronic dose (p=0.003).

CONCLUSION: GSK2256294 attenuates smoking related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.

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