Article

Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Trends in Pharmacological Sciences (Impact Factor: 9.99). 02/2007; 28(1):32-8. DOI: 10.1016/j.tips.2006.11.002
Source: PubMed

ABSTRACT Epoxyeicosatrienoic acids (EETs), derived from arachidonic acid by cytochrome P450 epoxygenases, are potent vasodilators that function as endothelium-derived hyperpolarizing factors in some vascular beds. EETs are rapidly metabolized by soluble epoxide hydrolase to form dihydroxyeicosatrienoic acids (DHETs). Recent reports indicate that EETs have several important non-vasomotor regulatory roles in the cardiovascular system. EETs are potent anti-inflammatory agents and might function as endogenous anti-atherogenic compounds. In addition, EETs and DHETs might stimulate lipid metabolism and regulate insulin sensitivity. Thus, pharmacological inhibition of soluble epoxide hydrolase might be useful not only for hypertension but also for abating atherosclerosis, diabetes mellitus and the metabolic syndrome. Finally, although usually protective in the systemic circulation, EETs might adversely affect the pulmonary circulation.

0 Followers
 · 
69 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Polyunsaturated fatty acids (PUFA) are oxidized by cytochrome P450 epoxygenases to PUFA epoxides which function as potent lipid mediators. The major metabolic pathways of PUFA epoxides are incorporation into phospholipids and hydrolysis to the corresponding PUFA diols by soluble epoxide hydrolase. Inhibitors of soluble epoxide hydrolase stabilize PUFA epoxides and potentiate their functional effects. The epoxyeicosatrienoic acids (EETs) synthesized from arachidonic acid produce vasodilation, stimulate angiogenesis, have anti-inflammatory actions, and protect the heart against ischemia-reperfusion injury. EETs produce these functional effects by activating receptor-mediated signaling pathways and ion channels. The epoxyeicosatetraenoic acids synthesized from eicosapentaenoic acid and epoxydocosapentaenoic acids synthesized from docosahexaenoic acid are potent inhibitors of cardiac arrhythmias. Epoxydocosapentaenoic acids also inhibit angiogenesis, decrease inflammatory and neuropathic pain, and reduce tumor metastasis. These findings indicate that a number of the beneficial functions of PUFA may be due to their conversion to PUFA epoxides. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 08/2014; 1851(4). DOI:10.1016/j.bbalip.2014.07.020 · 4.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and aimsThe hypothesis of this study was that microvascular flow-induced dilation (FID) and acetylcholine-induced dilation (AChID) is impaired in visceral (VAT) compared to subcutaneous adipose tissue (SAT) arterioles in morbidly obese women. Additional aim was to determine the mechanisms contributing to FID and AChID in VAT and SAT arterioles.Methods and resultsArterioles were obtained from SAT and VAT biopsies from women(BMI>35 kg/m2) undergoing bariatric surgery. Microvessels were cannulated for reactivity measurements in response to flow (pressure gradients of 10-100 cmH2O) and to acetylcholine (ACh;10-9-10-4 M) with and without Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin (INDO), and PEG-catalase. Nitric oxide (NO)and hydrogen peroxide (H2O2) generation were detected in arterioles by fluorescence microscopy. FID and AChID of arterioles from VAT were reduced compared to SAT arterioles.I n SAT arterioles,L-NAME, INDO, and PEG-catalase significantly reduced FID and AChID but had no effect individually on VAT arterioles’ vasodilator reactivity. INDO+L-NAME reduced FID in VAT arterioles. NO-fluorescence was greater in arterioles from SAT compared to VAT arterioles. Vascular H2O2 generation during flow was similar in both VAT and SAT.Conclusion Our results suggest that VAT arterioles display reduced vasodilator reactivity to flow and ACh compared to SAT arterioles, mediated by different regulatory mechanisms in human obesity.This article is protected by copyright. All rights reserved.
    Microcirculation (New York, N.Y.: 1994) 08/2014; 22(1). DOI:10.1111/micc.12164 · 2.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present experimental study was to assess the tocolytic effect of eicosanoids on myometrium from non-pregnant and pregnant rats with or without an induced inflammatory condition. Three hundred myometrial rings were obtained by median laparotomy from 50 Sprague-Dawley rats divided into three groups: (i) non-pregnant (n = 15); (ii) pregnant in absence (n = 20); or (iii) pregnant in presence (n = 15) of lipopolysaccharide treatment, timed at 22 days of pregnancy. Spontaneous contractile activities were compared by isometric tension measurements. The effects of epoxy- and hydroxyeicosanoids derived from arachidonic acid as well as specific enzyme inhibitors were assessed. Changes were expressed as percentage of basal activity by calculating the area under the curve as a function of drug concentration and compared to the effect of the vehicle. A decrease in contractile activity ranging 10-25% was observed upon addition of epoxy- and hydroxyeicosanoids. Increasing epoxyeicosanoid bioavailability by inhibiting their degradation induced a tocolytic effect in the non-pregnant group (20%) and in inflammation-induced condition (40%). There was a significant difference in reactivity between groups and pregnancy condition. Semiquantification of metabolic enzymes that produce (cytochrome P-450 epoxygenase) and degrade (soluble epoxide hydrolase) epoxyeicosanoids by western blot analysis revealed that these enzymes were mainly detected in the non-pregnant group. Eicosanoids can modify myometrial reactivity and their presence and effects are amplified in non-pregnant and in inflammation-induced condition. Our data suggest that in contrast to prostaglandins, epoxyeicosatrienoic acids are likely involved in the quiescence phase of parturition because they reduce the rhythmic contractile activity of uterine tissues in pregnant rats.
    Journal of Obstetrics and Gynaecology Research 12/2013; 40(3). DOI:10.1111/jog.12247 · 0.93 Impact Factor