Epoxyeicosatrienoic acids and endothelium-dependent responses

Campbell, William B.; Fleming, Ingrid

doi:10.1007/s00424-010-0804-6

Cited by 230 publications

(247 citation statements)

References 112 publications

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“…S4). Given that CYP enzymes are involved in the generation of endotheliumderived hyperpolarizing factor, which contributes to the shear stress-induced endothelium-dependent vasodilation (38,39), it will be important to elucidate the important role of LSS-activated PXR in the production of endothelium-derived hyperpolarizing factor. Nevertheless, physiological significance of flow-activated PXR awaits further investigation with the use of animal models with an EC-specific PXR overexpression or knockout approach.…”

Section: Discussionmentioning

confidence: 99%

Shear stress activation of nuclear receptor PXR in endothelial detoxification

Wang

Fang

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial cells (ECs) are constantly exposed to xenobiotics and endobiotics or their metabolites, which perturb EC function, as well as to shear stress, which plays a crucial role in vascular homeostasis. Pregnane X receptor (PXR) is a nuclear receptor and a key regulator of the detoxification of xeno-and endobiotics. Here we show that laminar shear stress (LSS), the atheroprotective flow, activates PXR in ECs, whereas oscillatory shear stress, the atheroprone flow, suppresses PXR. LSS activation of PXR in cultured ECs led to the increased expression of a PXR target gene, multidrug resistance 1 (MDR1). An in vivo study using rats showed that the expression of MDR1 was significantly higher in the endothelium from the descending thoracic aorta, where flow is mostly laminar, than from the inner curvature of aortic arch, where flow is disturbed. Functionally, LSSactivated PXR protects ECs from apoptosis triggered by doxorubicin via the induction of MDR1 and other detoxification genes. PXR also suppressed the expression of proinflammatory adhesion molecules and monocyte adhesion in response to TNF-α and lipopolysaccharide. Overexpression of a constitutively active PXR in rat carotid arteries potently attenuated proinflammatory responses. In addition, cDNA microarray revealed a large number of the PXR-activated endothelial genes whose products are responsible for major steps of detoxification, including phase I and II metabolizing enzymes and transporters. These detoxification genes in ECs are induced by LSS in ECs in a PXR-dependent manner. In conclusion, our results indicate that PXR represents a flow-activated detoxification system to protect ECs against damage by xeno-and endobiotics.hemodynamics | endothelial homeostasis | nuclear hormone receptor | gene regulation

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Section: Discussionmentioning

confidence: 99%

Shear stress activation of nuclear receptor PXR in endothelial detoxification

Wang

Fang

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Four regioisomeric EETs (14,15-, 11,12-, 8,9-and 5,6-EETs) are synthesized by cytochrome P450. In the vasculature, EETs are synthesized by the endothelium with 14,15-and 11,12-EET representing the predominant isomers (3,4). The EETs have actions on both endothelial cells (ECs) and smooth muscle cells (SMCs) (5).…”

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confidence: 99%

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

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Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein-coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40-overexpressing HEK293 cells (EC 50 = 0.58 ± 0.08 µM, 0.91 ± 0.08 µM, 3.9 ± 0.06 µM and 19 ± 0.37 nM, respectively). EETs with cisand trans-epoxides had similar activities, whereas substitution of a thiirane sulfur for the epoxide oxygen decreased the activities. 8,9-EET, 5,6-EET, and the epoxide hydrolysis products 11,12-and 14,15-vicdihydroxyeicosatrienoic acids were less active than 11,12-EET. The GPR40 antagonist GW1100 and siRNA-mediated GPR40 silencing blocked the EET-and GW9508-induced calcium increases. EETs are weak GPR120 agonists. GPR40 expression was detected in human and bovine endothelial cells (ECs), smooth muscle cells, and arteries. 11,12-EET concentration-dependently relaxed preconstricted coronary arteries; however, these relaxations were not altered by GW1100. In human ECs, 11,12-EET increased MAP kinase-mediated ERK phosphorylation, phosphorylation and levels of connexin-43 (Cx43), and expression of cyclooxygenase-2 (COX-2), all of which were inhibited by GW1100 and the MAP kinase inhibitor U0126. Moreover, siRNA-mediated GPR40 silencing decreased 11,12-EETinduced ERK phosphorylation. These results indicated that GPR40 is a low-affinity EET receptor in vascular cells and arteries. We conclude that epoxidation of arachidonic acid to EETs enhances GPR40 agonist activity and that 11,12-EET stimulation of GPR40 increases Cx43 and COX-2 expression in ECs via ERK phosphorylation. INTRODUCTIONhttp://www.jbc.org/cgi

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“…Therefore, this effect leads to reduced Ca 2+ influx through voltage‐dependent calcium channel (VDCCs), decrease in [Ca 2+ ] i and subsequent vasorelaxation. Another possible mechanism by which EETs activate TRPV4 receptor was provided by Campbell and Fleming 42. They concluded that EETs act on cells of the endothelium to enhance the influx of Ca 2+ by TRPV4.…”

Section: Discussionmentioning

confidence: 99%

11,12-Epoxyeicosatrienoic acid induces vasodilator response in the rat perfused mesenteric vasculature

Bihzad

Yousif

2017

Auton Autacoid Pharmacol

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Summary Epoxyeicosatrienoic acids (EETs) are endogenous ligands that undergo hydrolysis by soluble epoxide hydrolase (sEH). The responses of 11, 12‐EET in comparison with other vasodilator agonists including carbachol and sodium nitroprusside (SNP) were investigated. The effect of 1‐cyclohexyl‐3‐dodecyl urea (CDU), a sEH, was tested on the vasodilator effect induced by 11, 12‐EET in the perfused mesenteric beds isolated from normo‐glycaemic and type‐1 STZ‐diabetic rats.In the perfused mesenteric beds of control and diabetic animals, 11, 12‐EET produced vasodilation in a dose‐dependent manner. The vasodilator response induced by 11, 12‐EET was significantly decreased in tissues obtained from diabetic animals, but this was significantly corrected through inhibition of sEH.The effects of nitric oxide synthase inhibitor, cyclo‐oxygenase inhibitor, specific potassium channel inhibitors, soluble guanylyl cyclase inhibitor and transient receptor potential channel V4 inhibitor, on vasodilator response to 11, 12‐EET were investigated.In tissues isolated from control animals, vasodilator responses to 11, 12‐EET were not inhibited by acute incubation with l‐NAME, l‐NAME with indomethacin, glibenclamide, iberiotoxin, charybdotoxin, apamin or ODQ.Incubation with the transient receptor potential channel V4 inhibitor ruthenium red caused significantly reduced vasodilator responses induced by 11, 12‐EET.In conclusion, results from this study indicate that 11, 12‐EET has a vasodilator effect in the perfused mesenteric bed, partly through activation of vanilloid receptor. A strategy to elevate the levels of EETs may have a significant impact in correcting microvascular abnormality associated with diabetes.

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Epoxyeicosatrienoic acids and endothelium-dependent responses

Cited by 230 publications

References 112 publications

Shear stress activation of nuclear receptor PXR in endothelial detoxification

Shear stress activation of nuclear receptor PXR in endothelial detoxification

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

11,12-Epoxyeicosatrienoic acid induces vasodilator response in the rat perfused mesenteric vasculature

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