14,15-Epoxyeicosa-5(Z)-Enoic-mSI

Gauthier, Kathryn M.; Jagadeesh, S. G.; Falck, John R.; Campbell, William B.

doi:10.1161/01.hyp.0000091265.94045.c7

Cited by 48 publications

(44 citation statements)

References 42 publications

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“…The ability of 14,15-EEZE-mSI to block relaxation by 14,15-EET in rat middle cerebral artery is consistent with work in bovine coronary artery (Gauthier et al, 2003). Among the four regioisomers of EETs, 14,15-EEZE-mSI appears to be more selective for 14,15-EET and 5,6-EET (Gauthier et al, 2003), whereas 14,15-EEZE inhibits relaxation to all four regioisomers (Gauthier et al, 2002).The substantial inhibition of the LDF response to whisker stimulation with 14,15-EEZE-mSI is consistent with results showing that 14,15-EET is a major regioisomer synthesized in astrocytes (Alkayed et al, 1996;Amruthesh et al, 1993) and is either metabolized by epoxide hydrolase or incorporated into the phospholipid membrane (Shivachar et al, 1995).…”

Section: Epoxyeicosatrienoic Acidssupporting

confidence: 81%

“…Among the four regioisomers of EETs, 14,15-EEZE-mSI appears to be more selective for 14,15-EET and 5,6-EET (Gauthier et al, 2003), whereas 14,15-EEZE inhibits relaxation to all four regioisomers (Gauthier et al, 2002).The substantial inhibition of the LDF response to whisker stimulation with 14,15-EEZE-mSI is consistent with results showing that 14,15-EET is a major regioisomer synthesized in astrocytes (Alkayed et al, 1996;Amruthesh et al, 1993) and is either metabolized by epoxide hydrolase or incorporated into the phospholipid membrane (Shivachar et al, 1995). Because of its broad spectrum potency, 14,15-EEZE, rather than 14,15-EEZE-mSI, was chosen for testing interactions with adenosine and mGluR pathways.…”

Section: Epoxyeicosatrienoic Acidsmentioning

confidence: 89%

“…No further reductions in the response occurred after the second hour of superfusion. The EETs antagonist 14,15-EEZE-mSI, at a dose of 10 mmol/L, has been reported to inhibit relaxation of coronary artery rings to 14,15-EET (Gauthier et al, 2003). In isolated rat middle cerebral artery, 10 mmol/ L of 14,15-EEZE-mSI was found to reduce dilation to 100 and 300 nmol/L 14,15-EET ( Figure 5C; n = 4).…”

mentioning

confidence: 88%

“…Because preformed, stored EETs can be released from the phospholipid membrane (Shivachar et al, 1995), the EET antagonists 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) and 14,15-epoxyeicosa-5(Z)-enoic methylsulfonylimide (14,15-EEZE-mSI) were also used to confirm the role of EETs in this study (Gauthier et al, 2002(Gauthier et al, , 2003 and to test the interaction between EETs and adenosine pathways.…”

Section: Introductionmentioning

confidence: 99%

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Interaction of Mechanisms Involving Epoxyeicosatrienoic Acids, Adenosine Receptors, and Metabotropic Glutamate Receptors in Neurovascular Coupling in Rat Whisker Barrel Cortex

Shi

Liu

Gebremedhin

et al. 2007

J Cereb Blood Flow Metab

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Adenosine, astrocyte metabotropic glutamate receptors (mGluRs), and epoxyeicosatrienoic acids (EETs) have been implicated in neurovascular coupling. Although A 2A and A 2B receptors mediate cerebral vasodilation to adenosine, the role of each receptor in the cerebral blood flow (CBF) response to neural activation remains to be fully elucidated. In addition, adenosine can amplify astrocyte calcium, which may increase arachidonic acid metabolites such as EETs. The interaction of these pathways was investigated by determining if combined treatment with antagonists exerted an additive inhibitory effect on the CBF response. During whisker stimulation of anesthetized rats, the increase in cortical CBF was reduced by approximately half after individual administration of A 2B , mGluR and EET antagonists and EET synthesis inhibitors. Combining treatment of either a mGluR antagonist, an EET antagonist, or an EET synthesis inhibitor with an A 2B receptor antagonist did not produce an additional decrement in the CBF response. Likewise, the CBF response also remained reduced by B50% when an EET antagonist was combined with an mGluR antagonist or an mGluR antagonist plus an A 2B receptor antagonist. In contrast, A 2A and A 3 receptor antagonists had no effect on the CBF response to whisker stimulation. We conclude that (1) adenosine A 2B receptors, rather than A 2A or A 3 receptors, play a significant role in coupling cortical CBF to neuronal activity, and (2) the adenosine A 2B receptor, mGluR, and EETs signaling pathways are not functionally additive, consistent with the possibility of astrocytic mGluR and adenosine A 2B receptor linkage to the synthesis and release of vasodilatory EETs.

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Section: Epoxyeicosatrienoic Acidssupporting

confidence: 81%

Section: Epoxyeicosatrienoic Acidsmentioning

confidence: 89%

mentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interaction of Mechanisms Involving Epoxyeicosatrienoic Acids, Adenosine Receptors, and Metabotropic Glutamate Receptors in Neurovascular Coupling in Rat Whisker Barrel Cortex

Shi

Liu

Gebremedhin

et al. 2007

J Cereb Blood Flow Metab

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show abstract

“…While the receptor(s) for EETs have not yet been identified (4), EET antagonists are the most specific reagents available for pharmacologic suppression of EET activity (37,38) and have been used to antagonize the biological effects of EETs in other disease models (39)(40)(41)(42)(43). To determine whether an EET antagonist could prevent EET-induced metastasis, we co-administered the EET antagonist 14,15-EEZE-mSI with 14,15-EET following LLC primary tumor resection.…”

Section: Pharmacological Control Of Eets In Cancermentioning

confidence: 99%

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Panigrahy¹,

Edin²,

Lee³

et al. 2012

J. Clin. Invest.

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258

295

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Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.

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Epoxyeicosatrienoic acids and endothelium-dependent responses

Campbell

Fleming

2010

Pflugers Arch - Eur J Physiol

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230

225

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Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid that are produced by the vascular endothelium in response to agonists such as bradykinin and acetylcholine or physical stimuli such as shear stress or cyclic stretch. In the vasculature, the EETs have biological actions that are involved in the regulation of vascular tone, hemostasis and inflammation. In pre-constricted arteries in vitro, EETs activate calcium-activated potassium channels on vascular smooth muscle and the endothelium causing membrane hyperpolarization and relaxation. These effects are observed in a variety of arteries from experimental animals and humans; however, this is not a universal finding in all arteries. The mechanism of EET action may vary. In some arteries, EETs are released from the endothelium and are transferred to the smooth muscle where they cause potassium channel activation, hyperpolarization and relaxation through a G-protein coupled mechanism or transient receptor potential (TRP) channel activation. In other arteries, EETs activate TRP channels on the endothelium to causes endothelial hyperpolarization that is transferred to the smooth muscle by gap junctions or potassium ion. Some arteries use a combination of mechanisms. Acetylcholine and bradykinin increase blood flow in dogs and humans that is inhibited by potassium channel blockers and cytochrome P450 inhibitors. Thus, the EETs are endothelium-derived hyperpolarizing factors mediating a portion of the relaxations to acetylcholine, bradykinin, shear stress and cyclic stretch and regulate vascular tone in vitro and in vivo.

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14,15-Epoxyeicosa-5(Z)-Enoic-mSI

Cited by 48 publications

References 42 publications

Interaction of Mechanisms Involving Epoxyeicosatrienoic Acids, Adenosine Receptors, and Metabotropic Glutamate Receptors in Neurovascular Coupling in Rat Whisker Barrel Cortex

Interaction of Mechanisms Involving Epoxyeicosatrienoic Acids, Adenosine Receptors, and Metabotropic Glutamate Receptors in Neurovascular Coupling in Rat Whisker Barrel Cortex

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Epoxyeicosatrienoic acids and endothelium-dependent responses

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