Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart

Gross, Garrett J.; Gauthier, Kathryn M.; Moore, Jeannine; Falck, John R.; Hammock, Bruce D.; Campbell, William B.; Nithipatikom, Kasem

doi:10.1152/ajpheart.00186.2008

Cited by 79 publications

(88 citation statements)

References 30 publications

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“…5 and 7), as both iNOS and COX2 activation are considered essential for the protective effects of the delayed form of ischemic preconditioning (45) and the IS-limiting effects of statins (7,50). Eicosanoids, both COX2 dependent, such as PGI 2 (37), and COX2 independent, such as 11,12-epoxyeicosatrienoic acid and 14,15-epoxyeicosatrienoic acid (16,17), have been reported to reduce myocardial IS. However, the role of iNOS and COX2 in mediating immediate protection against reperfusion injury (such as postconditioning), in contrast to a more prolonged stimulus such as delayed ischemic preconditioning or pretreatment with statins, is less established (23,37).…”

Section: Discussionmentioning

confidence: 99%

Resolvin E1 protects the rat heart against reperfusion injury

Keyes

Lin

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

147

102

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The purpose of the present study was to assess whether resolvin E1 (RvE1), an anti-inflammatory mediator derived from eicosapentaenoic acid, would limit myocardial infarct size in the rat. The H9c2 cell line was used to assess whether RvE1 has direct protective effects on cardiomyocytes. In in vivo experiments, Male Sprague-Dawley rats underwent 30 min of ischemia/4 h of reperfusion. Before reperfusion, rats received intravenous RvE1 (0, 0.03, 0.1, or 0.3mg/kg). In in vitro experiments, H9c2 cells were incubated with RvE1 (0, 1, 10, 100, or 1000 nM). Cells were subjected to 18 h of incubation under normoxic conditions, 16 h of hypoxia, or 16 h of hypoxia and 2 h of reoxygenation. In vivo, RvE1 dose dependently reduced infarct size (30.7 ± 1.7% of the area at risk in the control group and 29.1 ± 1.6%, 14.7 ± 1.3%, and 9.0 ± 0.6% in the 0.03, 0.1, and 0.3 mg/kg groups, respectively, P < 0.001). In vitro, RvE1 increased viability and decreased apoptosis in a dose-dependent fashion in cells exposed to hypoxia or hypoxia/reoxygenation. A maximal effect was achieved at a concentration of 100 nM. RvE1 augmented phosphoinositide 3-kinase activity, attenuated caspase-3 activity, and augmented calcium-dependent nitric oxide synthase activity in cells exposed to hypoxia or hypoxia/reoxygenation. RvE1 increased Akt, ERK1/2, and endothelial nitric oxide synthase phosphorylation and attenuated the levels of activated caspase-3 and phosphorylated p38 levels. AG-1478, an EGF receptor tyrosine kinase inhibitor, blocked the protective effect of RvE1 both in vivo and in vitro and attenuated the RvE1-induced increase in Akt and ERK1/2 phosphorylation. In conclusion, RvE1, an anti-inflammatory mediator derived from eicosapentaenoic acid, has a direct protective effect on cardiomyocytes against ischemia-reperfusion injury and limits infarct size when administered intravenously before reperfusion.

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Section: Discussionmentioning

confidence: 99%

Resolvin E1 protects the rat heart against reperfusion injury

Keyes

Lin

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

147

102

View full text Add to dashboard Cite

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“…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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“…11,12-and 14,15-EET have cardioprotective effects during reoxygenation of ischemic myocardium, and they decrease infarct size (8,34). Several mechanisms have been reported to mediate the cardioprotective effect, including activation of myocardial K ATP channels by decreasing their sensitivity to ATP (35), activation of K ATP channels by triggering a burst of reactive oxygen species (36), and activation of a PI3K/Akt pro-survival pathway (37).…”

Section: Eet-activated Signaling Pathwaysmentioning

confidence: 99%

Arachidonic acid cytochrome P450 epoxygenase pathway

Spector

2009

Journal of Lipid Research

356

311

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Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET, that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activating smooth muscle large-conductance Ca 21 -activated K 1 channels (BK Ca ). In addition, they have anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. CYP epoxygenases also convert eicosapentaenoic acid to vasoactive epoxy-derivatives, and endocannabinoids containing 11,12-and 14,15-EET are formed. Many EET actions appear to be initiated by EET binding to a membrane receptor that activates ion channels and intracellular signal transduction pathways. However, EETs also are taken up by cells, are incorporated into phospholipids, and bind to cytosolic proteins and nuclear receptors, suggesting that some functions may occur through direct interaction of the EET with intracellular effector systems. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs). Because this attenuates many of the functional effects of EETs, sEH inhibition is being evaluated as a mechanism for increasing and prolonging the beneficial actions of EETs. Epoxyeicosatrienoic acids (EET) are epoxide derivatives of arachidonic acid. They are formed by cytochrome P450 (CYP) epoxygenases and function as lipid mediators. Epoxidation can occur at any of the four double bonds of arachidonic acid, giving rise to four regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET. EETs are synthesized in the endothelium and activate large-conductance Ca 21 -activated K 1 channels (BK Ca ), causing hyperpolarization of the vascular smooth muscle and vasorelaxation. Thus, EETs function as an endothelium-derived hyperpolarizing factor (EDHF) in a number of vascular beds, including the coronary and renal circulations, producing a decrease in blood pressure. Soluble epoxide hydrolase (sEH), which converts EETs to dihydroxyeicosatrienoic acids (DHETs), attenuates many of the functional effects of EETs. These seminal findings have been described in a number of detailed reviews (1-4). Recent results with cultured cells and animal models indicate that EETs have additional potentially beneficial effects on the vascular system, heart, kidneys, and nervous system, and many current studies are directed at these actions (5-9). The other current emphasis is on sEH inhibition as a therapeutic strategy for increasing the beneficial effects of EETs (10, 11). EET SYNTHESIS, METABOLISM, AND FUNCTIONEETs are synthesized by cells that express CYP epoxygenase activity. As illustrated in Fig. 1, these enzymes act on arachidonic acid released from phospholipids when cytosolic phospholipase A 2 (cPLA 2 ) is activated (12). The epoxygenase inserts an oxygen atom on a carbon attached to one of the double bonds of arachidonic acid, and the double bond is reduced as the epoxide forms. Each CYP epoxygenase produces several regioisomers, with one for...

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Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart

Cited by 79 publications

References 30 publications

Resolvin E1 protects the rat heart against reperfusion injury

Resolvin E1 protects the rat heart against reperfusion injury

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Arachidonic acid cytochrome P450 epoxygenase pathway

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