Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers

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

doi:10.1016/j.chest.2016.10.058

Abstract

BackgroundSmoking and 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 that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo.MethodsEndogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers.ResultsCompared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (–8.33 ± 0.172 logM vs –8.10 ± 0.118 logM; P = .001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003).ConclusionsGSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.Trial RegistryClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov

Highlights

Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction
epoxyeicosatrienoic acid (EET) are synthesized by cytochrome P450 (CYP) enzymes, and metabolized to their less biologically active diols by soluble epoxide hydrolase enzymes.[12]
There was a trend toward a higher plasma concentration of the basal EET/DHET ratio in the matched control group 1 compared with patients with COPD (0.54 Æ 0.12 vs 0.45 Æ 0.14; P 1⁄4 .08) (Fig 1)

Summary

Methods

Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers. Analysis and statistical methods are described in e-Appendix 1. We used forearm venous occlusion plethysmography[21] to assess vascular function in vivo with intraarterial infusion of challenge agents through a 27-gauge needle (Coopers Needleworks) inserted. Venous plasma concentrations of EET/DHET were assessed as representative of sEH activity at baseline and during the forearm blood flow studies. Detailed methods and statistical analyses can be seen in e-Appendix 1

Results

Discussion

Conclusion