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Original Research |

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

Lucy Yang, MBChB; Joseph Cheriyan, FRCP; David D. Gutterman, MD; Ruth J. Mayer, PhD; Zsuzsanna Ament, PhD; Jules L. Griffin, PhD; Aili L. Lazaar, MD; David E. Newby, FRCP; Ruth Tal-Singer, PhD; Ian B. Wilkinson, FRCP
Author and Funding Information

Summary of conflict of interest statements:

JC is employed by Cambridge University Hospitals NHS Foundation Trust and spends 50% of his time on GSK clinical trial research, but receives no GSK benefits. DEN has received consultancy fees from GSK. IBW has received academic grants from GSK. RM, AL, and RTS are GSK employees and shareholders.

Funding information:

This work was supported by GSK [SEH114068] and Innovate UK (ERICA Consortium 10037625), the Wellcome Trust grant numbers 100780/Z/12/Z, and WT103782AIA awarded to LY, and DEN respectively; the Raymond and Beverley Sackler fellowship awarded to LY; National Institute for Health Research funding awarded to IBW, and JC in the Cambridge Comprehensive Biomedical Research, and the British Heart Foundation grant numbers CH/09/002, and RG66885 RCZA/008 awarded to DEN, and IBW. JLG and ZA are funded by the Medical Research Council (Medical Research Council Lipid Profiling and Signalling, MC UP A90 1006 & Lipid Dynamics and Regulation, MC PC 13030).

Notation of prior abstract publication / presentation:

Safety and pharmacology of a soluble epoxide hydrolase inhibitor European Respiratory Journal 2015;46:suppl 59. Presented at European Respiratory Society meeting, Amsterdam, September 2015

The role of epoxyeicosatrienoic acids in regulating endothelial function and the effects of a novel soluble epoxide hydrolase inhibitor in humans. Presented at the British Pharmacological Society winter pharmacology meeting, London, December 2015, and winner of the Pfizer poster prize.

The role of epoxyeicosatrienoic acids in regulating endothelial function and the effects of a novel soluble epoxide hydrolase inhibitor GSK2256294 in humans. J Am Coll Cardiol 2016;67(13_S):2308-2308. Presented at American College of Cardiology annual meeting, Chicago, April 2016

Trial Registration: ClinicalTrials.gov NCT01762774

1Experimental Medicine & Immunotherapeutics (EMIT), University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK

2Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK

3Clinical Unit Cambridge, GSK R&D, Cambridge CB2 0GG, UK

4Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA

5GSK R&D, King of Prussia, PA, USA

6MCR Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL & Department of Biochemistry, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA

7British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, EH16 4SB, UK

Correspondence: Dr. Joseph Cheriyan, EMIT, University of Cambridge, Addenbrooke’s Hospital, UK.


Copyright 2016, . All Rights Reserved.


Chest. 2016. doi:10.1016/j.chest.2016.10.058
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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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