14,15-Epoxyeicosatrienoic acid induces vasorelaxation through the prostaglandin EP2 receptors in rat mesenteric artery

Yang, Cui; Kwan, Yiu Wa; Au, Alice Lai-Shan; Poon, Chi‐Ming; Zhang, Qian; Chan, Shun‐Wan; Lee, Simon Ming‐Yuen; Leung, George Pak-Heng

doi:10.1016/j.prostaglandins.2010.06.004

Cited by 34 publications

(30 citation statements)

References 43 publications

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“…In rodent arteries, EP receptors are low affinity receptors for 14,15-EET; however, the K i 's for 14,15-EET on the four EP receptors range from 11-40 µM (28,29,56). Thus, 20-70-fold more 14,15-EET is required to activate EP receptors than GPR40.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…EET also activate prostaglandin E type-2 (EP2) receptors in µM concentrations (28,29). The transient receptor potential vanlloid-1 (TRPV1) channel has been proposed to represent the vascular EET receptor; however, there is no evidence for an EET binding site on this channel (30).…”

mentioning

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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“…In this regard, some EET responses involve receptors for other lipid mediators. For example, 14,15-EET produced vasodilation of rat mesenteric artery by activation of the prostaglandin EP 2 receptor[104]. 14,15-EET also relaxed the aorta and mesenteric resistance arteries by acting as an antagonist of the thromboxane receptor [105].…”

Section: Mechanism Of Pufa Epoxide Actionmentioning

confidence: 99%

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

Spector

Kim

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

198

172

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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.

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“…This is currently unknown, but in the few situations in which the epoxides and diols have been directly compared, the diols are generally found to be less active [48]. Whether or not EET (and/or DHET) receptors will be found among the current orphan receptors is unclear as it is equally possible that fatty acid epoxides bind to other lipid mediator receptors such as the EP 2 prostaglandin receptor [49] or the thromboxane receptor [50]. These interactions have, however, only been superficially studied to date.…”

Section: Molecular Effector Mechanismsmentioning

confidence: 99%

The cytochrome P450 pathway in angiogenesis and endothelial cell biology

Fleming

2011

Cancer Metastasis Rev

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Long thought to be biologically important only as xenobiotic metabolizing enzymes, it is now clear that extrahepatic cytochrome P450 epoxygenases can utilize endogenous substrates such as arachidonic acid, linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid to generate bioactive lipid mediators. The epoxides thus generated can acutely affect vascular tone, and stimulate a spectrum of signaling pathways that affect growth-promoting kinase and transcription factor activity in vascular as well as cancer cells. Endogenous epoxide levels are largely controlled by the activity of the soluble epoxide hydrolase, and specific inhibitors of the enzyme as well as knockout mice are helping to determine the roles of these lipids in physiological and pathological angiogenesis. This review summarizes current knowledge on the aspects of the cytochrome P450/soluble epoxide hydrolase pathway related to vascular homeostasis and cancer.

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14,15-Epoxyeicosatrienoic acid induces vasorelaxation through the prostaglandin EP2 receptors in rat mesenteric artery

Cited by 34 publications

References 43 publications

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

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

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

The cytochrome P450 pathway in angiogenesis and endothelial cell biology

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