Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients

Thomas Duflot,Julien Wils,Lucile Moreau-Grangé,Christophe Morisseau,Clothilde Roche,Jérémy Bellien,Robinson Joannidès,Sylvanie Renet,Fabien Lamoureux,Dongyang Li,Matthieu Leuillier,Vincent Richard,Anne-Françoise Cailleux,Isabelle Rémy-Jouet,Gaëtan Prévost,Michèle Iacob

doi:10.1186/s12933-019-0843-z

Abstract

BackgroundThis pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.Methods and resultsRadial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating.ConclusionsThese results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations.Trial registration NCT02311075. Registered December 8, 2014.

Highlights

This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase, which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes
These results demonstrate that an increased EETs degradation by soluble epoxide hydrolase (sEH) and altered nitric oxide (NO) bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hyperten‐ sive status
Besides NO, we and others have shown in animal models of insulin resistance and diabetes that a decreased in epoxyeicosatrienoic acids (EETs) availability may be a main contributor to this endothelial dysfunction [3, 4]

Summary

Introduction

This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes. Besides NO, we and others have shown in animal models of insulin resistance and diabetes that a decreased in epoxyeicosatrienoic acids (EETs) availability may be a main contributor to this endothelial dysfunction [3, 4]. SEH inhibitors have been shown to improve endothelial function and metabolic homeostasis in animal models of diabetes [3, 8], and correlation studies suggested that the more EETs bioavailability is elevated the less insulin sensitivity is altered in humans [9]. No study has investigated whether the alteration of EETs pathway is involved in the endothelial dysfunction of diabetic patients, which could strengthen the interest of using sEH inhibitors in this population

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