Inside epoxyeicosatrienoic acids and cardiovascular disease - PubMed (original) (raw)

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Inside epoxyeicosatrienoic acids and cardiovascular disease

Stefania Tacconelli et al. Front Pharmacol. 2014.

Abstract

Epoxyeicosatrienoic acids (EETs) generated from arachidonic acid through cytochrome P450 (CYP) epoxygenases have many biological functions. Importantly, CYP epoxygenase-derived EETs are involved in the maintenance of cardiovascular homeostasis. In fact, in addition to their potent vasodilating effect, EETs have potent anti-inflammatory properties, inhibit platelet aggregation, promote fibrinolysis, and reduce vascular smooth muscle cell proliferation. All EETs are metabolized to the less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Numerous evidences support the role of altered EET biosynthesis in the pathophysiology of hypertension and suggest the utility of antihypertensive strategies that increase CYP-derived EET or EET analogs. Indeed, a number of studies have demonstrated that EET analogs and sEH inhibitors induce vasodilation, lower blood pressure and decrease inflammation. Some of these agents are currently under evaluation in clinical trials for treatment of hypertension and diabetes. However, the role of CYP epoxygenases and of the metabolites generated in cancer progression may limit the use of these drugs in humans.

Keywords: cytochrome P450; epoxyeicosatrienoic acids; epoxygenases; hypertension; soluble epoxide hydrolase.

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Figures

FIGURE 1

FIGURE 1

The cascade of arachidonic acid (AA). AA is a polyunsaturated omega-6 fatty acid which is released from the sn2 position of membrane phospholipids by the activity of cPLA2. Free AA can be metabolized to eicosanoids through three major pathways: the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway, and the cytochrome P450 (CYP) pathway. In the CYP pathway, AA is converted to epoxyeicosatrienoic acids (EETs) and 20-HETE by CYP epoxygenases and CYP ω-hydroxylases, respectively. All EETs are then further metabolized by soluble epoxide hydrolase (sEH) forming the less active dihydroxyeicosatrienoic acids (DHETs). Modified from Imig and Hammock (2009).

FIGURE 2

FIGURE 2

Biological effects of EETs.

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