Insulin resistance and endothelial dysfunction: Are epoxyeicosatrienoic acids the link?

Abstract

Epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolites of arachidonic acid, are potent vasodilators and are believed to be the endothelium-derived hyperpolarizing factor in a number of vascular beds. In addition, EETs may play a role in the secretion and action of insulin and the metabolism of carbohydrates and lipids. Pharmacological manipulation of EETs may be a useful therapeutic approach for disease states such as hypertension, diabetes mellitus and the metabolic syndrome. EET mimetics and antagonists and drugs that increase EET synthesis or decrease their degradation are currently under investigation. The cellular mechanism of action of EETs appears to be complex and is being intensively studied by a number of investigators. In the present article, EET production, metabolism, isomerism and vasodilatory effects will be reviewed and potential mechanisms of action discussed. The role of EETs in insulin secretion and sensitivity and their implication in diabetes mellitus and the metabolic syndrome will also be reviewed. Drugs affecting EET bioavailability and action may be promising agents to use to treat hypertension/insulin resistance. The effects of these agents in experimental vascular disorders will also be discussed.

Keywords: Endothelium; Epoxyeicosatrienoic acids; Insulin; Soluble epoxide hydrolase; Vasodilation.

Figure 1)

Summary of the production, isomerism and metabolism of epoxyeicosatrienoic acids

Figure 2)

Production of epoxyeicosatrienoic acids from endocannabinoids

Figure 3)

Chemical structure of the regioisomer-specific epoxyeicosatrienoic acid antagonist, 14,15-epoxyeicosa-5(Z)-enoic-methylsulfonylimide

Figure 4)

Postulated mechanisms of action of epoxyeicosatrienoic acids (EETs) on vascular tone. Stimuli such as agonists or physical forces activate endothelial phospholipase A₂ (PLA₂) that either releases preformed EETs from their storage sites on phospholipids or the release of arachidonic acid (AA). AA is then converted to EETs by the action of Cytochrome P450 (CYP) epoxygenases. Both nitric oxide (NO) and hydrogen peroxide (H₂O₂) inhibit the CYP-mediated production of EETs. EETs then act in an autocrine manner inducing protein kinase A, which results in the translocation of TRPC6 channels to caveolin-1 rich areas of the endothelial cell membrane where they are activated and cause Ca²⁺ entry. This leads to the activation of intermediate conductance calcium-activated potassium channels (IKCa) and small conductance calcium-activated potassium channels (SKCa) with subsequent K⁺ efflux and endothelial hyperpolarization, which can then be transferred to the smooth muscle. EETs can also activate transient receptor potential channels (TRPV4) on vascular smooth muscle cells (VSMCs) leading to Ca²⁺ influx, which activates Ca²⁺ release from intracellular stores through ryanodine (Ry) receptors followed by activation of large conductance calcium-activated potassium (BKCa) channels. EETs can also directly activate BKCa, protein phosphatase 2A cell-signalling could be involved in this mechanism, or activate them through GS protein-coupled receptors. EETs also stimulate endothelial nitric oxide synthase (eNOS) and NO production, NO, in contrast, inhibits production of EETs. H₂O₂ is an endothelium-derived hyperpolarizing factor that inhibits EET production and causes vasorelaxation. EETs are also involved in A_2A adenosine receptor-mediated relaxation. Finally, EETs cause vasodilation through competitive inhibition of thromboxane (TX) receptor and inhibition of volume-activated chloride channels (VACC) in a cGMP/cAMP-dependent mechanism