The role of epoxyeicosatrienoic acids in regulating endothelial function and the effects of a novel soluble epoxide hydrolase inhibitor in humans

Introduction: Chronic obstructive pulmonary disease (COPD) patients are at higher risk of developing cardiovascular disease, attributable to effects of smoking, chronicsystemic inflammation, and endothelial dysfunction. Like nitric oxide (NO), epoxyeicosatrienoic acids (EETs) synthesised in the endothelial cells also regulate vascular tone and can attenuate inflammation. Impaired EETs signalling may have deleterious effects, and inhibiting its metabolism by soluble epoxide hydrolase (sEH) enzyme, may modulate cardioprotection. We hypothesised that EETs signalling is impaired in COPD, and sEH inhibition may improve endothelial function in subjects with EETs mediated endothelial dysfunction.

Methods: We used for earmplethy smography to interrogate endothelial function in 2 exploratory medicine studies, including a first-time-in-human (FTIH) trial using a novels EH inhibitor (GSK2256294) for proof of mechanism (GSK funded; NCT01762774). Firstly, we assessedendothelial function in COPD patients (n=12), and healthy controls (n=12)by measuring forearmblood flow (FBF) responses to bradykinin(BK), basal EETs tone by response to fluconazole (inhibits EETs synthesis), and stimulated EETs response by BK co-infused with fluconazole. In the FTIH trial, we assessed the effects of 14 days dosing with oral GSK2256294 (6mg and 18mg) in 2 cohorts of otherwise healthy overweight smokers as a paradigm of COPD (n=11 active in each, n=6 placebo). Responses to BK under NO and prostacyclin inhibition (with NG-monomethyl-L-arginine and aspirin) were assessed pre-dose, and after Day 1, and Day 14 dosing. FBF ratio (infused: non-infused) are presented asmean±SEM. Data were analysed by repeated measures ANOVA. Treatment effect in the FTIH were analysed separately in the active drug, and placebo cohorts due to unequal randomisation (absolute flow: primary analysis, FBF ratio: post-hoc)

Results: Basal EETs tone was impaired in COPD patients, as shown by 25±6.86% less vasoconstriction to fluconazole compared with controls (p=0.01). COPD patients exhibited endothelial dysfunction, as vasodilation was 35.43±14.18% less than controls (*p=0.001), and stimulated EETs mediated response was impaired in COPD, as fluconazole inhibited BK response by 26.02±7.90% in controls (§p=0.008), but did not change in COPD (Fig. A). With 6mg sEH inhibition, forearm responses to BK increased by 38.38±17.44% on Day 1 (*p=0.02), and 21.05±11.80% on day 14 (§p=0.0002) (Fig. B). At 18mg, responses increased by 26.76±19.28% on day 1 (*p=0.001), and 27.13±15.65% on day 14 (p=0.37) (Fig. C). There were no significant changes in the placebo group on both day 1 and day 14.

Conclusions: EETs pathway is impaired in COPD patients, and sEH inhibition ameliorates EETs mediated endothelial dysfunction in otherwise healthy overweight smokers. sEH inhibition may be a novel therapeutic target for similar populations, including COPD.