Linoleic acid metabolites act to increase contractility in isolated rat heart

Mitchell, Lex A.; Grant, David F.; Melchert, Russell B.; Petty, Nathan; Kennedy, Richard H.

doi:10.1007/s12012-002-0006-3

Cited by 17 publications

(11 citation statements)

References 37 publications

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“…The main caveat of these studies, which reported that EpOMEs and DiHOMEs have toxic effects, is that very high concentrations (100–500 μM) were used [48]. Contrary to these reports, lower, more physiological concentrations of EpOMEs and DiHOMEs did not have toxic effects and rather had beneficial effects [61]. Mitchell et al reported that LA and its oxidative metabolites (EpOMEs and DiHOMEs) did not have toxic effects during acute exposure in Langendorff-perfused rat hearts [61].…”

Section: Discussionmentioning

confidence: 99%

“…Contrary to these reports, lower, more physiological concentrations of EpOMEs and DiHOMEs did not have toxic effects and rather had beneficial effects [61]. Mitchell et al reported that LA and its oxidative metabolites (EpOMEs and DiHOMEs) did not have toxic effects during acute exposure in Langendorff-perfused rat hearts [61]. Pretreatment with 12,13-EpOME protected primary cultures of rabbit renal proximal tubular cells against hypoxia/reoxygenation injury [62].…”

Section: Discussionmentioning

confidence: 99%

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Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ

et al. 2016

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Coronary reactive hyperemia (CRH) is a physiological response to ischemic insult that prevents the potential harm associated with an interruption of blood supply. The relationship between the pharmacologic inhibition of soluble epoxide hydrolase (sEH) and CRH response to a brief ischemia is not known. sEH is involved in the main catabolic pathway of epoxyeicosatrienoic acids (EETs), which are converted into dihydroxyeicosatrienoic acids (DHETs). EETs protect against ischemia/reperfusion injury and have numerous beneficial physiological effects. We hypothesized that inhibition of sEH by t-AUCB enhances CRH in isolated mouse hearts through changing the oxylipin profiles, including an increase in EETs/DHETs ratio. Compared to controls, t-AUCB–treated mice had increased CRH, including repayment volume (RV), repayment duration, and repayment/debt ratio (p < 0.05). Treatment with t-AUCB significantly changed oxylipin profiles, including an increase in EET/DHET ratio, increase in EpOME/DiHOME ratio, increase in the levels of HODEs, decrease in the levels of mid-chain HETEs, and decrease in prostanoids (p < 0.05). Treatment with MS-PPOH (CYP epoxygenase inhibitor) reduced CRH, including RV (p < 0.05). Involvement of PPARγ in the modulation of CRH was demonstrated using a PPARγ-antagonist (T0070907) and a PPARγ-agonist (rosiglitazone). T0070907 reduced CRH (p < 0.05), whereas rosiglitazone enhanced CRH (p < 0.05) in isolated mouse hearts compared to the non-treated. These data demonstrate that sEH inhibition enhances, whereas CYP epoxygenases-inhibition attenuates CRH, PPARγ mediate CRH downstream of the CYP epoxygenases-EET pathway, and the changes in oxylipin profiles associated with sEH-inhibition collectively contributed to the enhanced CRH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ

et al. 2016

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“…However, the only lipids that were further increased in Tie2‐CYP2C8 Tr hearts compared to WT were 9,10‐ and 12,13‐DiHOME. At high levels (>10 μM), the EpOMEs or DiHOMEs have been reported to have a variety of effects, including cytotoxicity to renal tubules (31), stimulation of ROS production (32), increased contractility in rat hearts (52), cardiodepression in dogs (34), inhibition of papillary muscle contraction, and vasoconstriction of isolated arteries (33). To examine the role of DiHOMEs on functional outcomes after I/R, we treated WT hearts with physiologically relevant concentrations (250 nM) of 9,10‐DiHOME.…”

Section: Discussionmentioning

confidence: 99%

Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia‐reperfusion injury in isolated mouse heart

et al. 2011

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Cytochrome P450 (CYP) epoxygenases CYP2C8 and CYP2J2 generate epoxyeicosatrienoic acids (EETs) from arachidonic acid. Mice with expression of CYP2J2 in cardiomyocytes (αMHC-CYP2J2 Tr) or treated with synthetic EETs have increased functional recovery after ischemia/reperfusion (I/R); however, no studies have examined the role of cardiomyocyte- vs. endothelial-derived EETs or compared the effects of different CYP epoxygenase isoforms in the ischemic heart. We generated transgenic mice with increased endothelial EET biosynthesis (Tie2-CYP2C8 Tr and Tie2-CYP2J2 Tr) or EET hydrolysis (Tie2-sEH Tr). Compared to wild-type (WT), αMHC-CYP2J2 Tr hearts showed increased recovery of left ventricular developed pressure (LVDP) and decreased infarct size after I/R. In contrast, LVDP recovery and infarct size were unchanged in Tie2-CYP2J2 Tr and Tie2-sEH Tr hearts. Surprisingly, compared to WT, Tie2-CYP2C8 Tr hearts had significantly reduced LVDP recovery (from 21 to 14%) and increased infarct size after I/R (from 51 to 61%). Tie2-CYP2C8 Tr hearts also exhibited increased reactive oxygen species (ROS) generation, dihydroxyoctadecenoic acid (DiHOME) formation, and coronary resistance after I/R. ROS scavengers and CYP2C8 inhibition reversed the detrimental effects of CYP2C8 expression in Tie2-CYP2C8 Tr hearts. Treatment of WT hearts with 250 nM 9,10-DiHOME decreased LVDP recovery compared to vehicle (16 vs. 31%, respectively) and increased coronary resistance after I/R. These data demonstrate that increased ROS generation and enhanced DiHOME synthesis by endothelial CYP2C8 impair functional recovery and mask the beneficial effects of increased EET production following I/R.

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“…Their significance is unclear. The literature on LA oxylipins is limited and inconsistent; some, but not all, preclinical studies suggest these oxylipins are cardiotoxic [ 33 ]. Analysis of the EpOME/DiHOME and EpETE/DiHETE ratio for any NSAID use versus no NSAID use in all subjects or sex-stratified analyses were null (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Celecoxib use and circulating oxylipins in a colon polyp prevention trial

et al. 2018

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Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E2 are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (P<0.05) and differences were greater among non-aspirin users. LOX derived 5- and 8-HETE were elevated with celecoxib and positively associated with systolic blood pressure (P = 0.011 and P = 0.019 respectively). 20-HETE, a prohypertensive androgen-sensitive CYP450 metabolite was higher with celecoxib absent aspirin and was positively associated with SBP in men (P = 0.040) but not women. Independent of celecoxib or aspirin, LOX derived metabolites from ARA were strongly associated with SBP including 5- and 8-HETE. These findings support oxylipins, particularly the ARA LOX-derived, in blood pressure control and indicate that pharmacologic inhibition of COX-2 has effects on LOX and CYP450 ARA metabolism that contribute to hypertension in some patients.

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Linoleic acid metabolites act to increase contractility in isolated rat heart

Cited by 17 publications

References 37 publications

Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ

Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ

Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia‐reperfusion injury in isolated mouse heart

Celecoxib use and circulating oxylipins in a colon polyp prevention trial

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