Direct cardiovascular actions of two metabolites of linoleic acid

Siegfried, Martin R.; Aoki, Naoto; Lefer, A M; Elisseou, E. Michael; Zipkin, Robert E.

doi:10.1016/0024-3205(90)90086-7

Cited by 28 publications

(20 citation statements)

References 10 publications

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“…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. This dose is much lower than that used in previous experiments (31)(32)(33)(34) but is similar to that which can be found during sepsis (53) or in burn victims (54). While we observed no significant changes in coronary resistance, heart rate, or LVDP prior to ischemia, 9,10-DiHOME significantly reduced functional recovery after ischemia.…”

Section: Discussionsupporting

confidence: 76%

“…48). Thus, CYP2J2 is more likely to metabolize arachidonic acid to cardioprotective EETs, whereas CYP2C8 is more likely to metabolize linoleic acid to EpOMEs, which on conversion by sEH to DiHOMEs, have cytotoxic and cardiodepressive effects (33, 34, 49).…”

Section: Discussionmentioning

confidence: 99%

“…CYP2C epoxidation of linoleic acid also generates leukotoxins or epoxyoctadecaenoic acids (EpOMEs), which are converted by sEH to toxic compounds called leukotoxin diols or dihydroxyoctadecaenoic acids (DiHOMEs) (30). Leukotoxins and leukotoxin diols have been reported to be cytotoxic (31, 32), vasoconstrictive (33), and cardiodepressive (34). Thus, it is unclear whether enhanced CYP2C activity during I/R is beneficial via increased EET production, or detrimental via increased production of ROS and DiHOMES.…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…10 Leukotoxins constrict carotid arteries and reduce the strength of contraction of myocardium from cats. 11 Some of these effects may be mediated by nitric oxide released in response to the lipids. 12 It is probable that the reported effects of leukotoxins are not mediated by the epoxides themselves, but by their hydrolysis products, the corresponding diols.…”

Section: Discussionmentioning

confidence: 99%

An oxidized derivative of linoleic acid affects aldosterone secretion by adrenal cells in vitro

Goodfriend¹,

Ball²,

Gardner³

2002

Prostaglandins, Leukotrienes and Essential Fatty Acids

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“…Elevated EpOME levels are observed in lungtissue and lavage after experimental exposure of rats to inhaled oxidants (Sevanian et al 1979). In animal models, administration of EpOME causes pulmonary oedema, vasodilation and cardiac failure, suggesting the possibility that EpOME-associated toxicity contributes to ARDS (Ishizaki et al 1995;Siegfried et al 1990;Sugiyama et al 1987;Hu et al 1988).…”

Section: Introductionmentioning

confidence: 99%

Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

Hammock

2007

J Biosci

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The leukotoxins [9(10)-and 12(13)-EpOME] are produced by activated inflammatory leukocytes such as neutrophils. High EpOME levels are observed in disorders such as acute respiratory distress syndrome and in patients with extensive burns. Although the physiological significance of the EpOMEs remains poorly understood, in some systems, the EpOMEs act as a protoxin, with their corresponding epoxide hydrolase metabolites, 9,10-and 12,13-DiHOME, specifically exerting toxicity. Both the EpOMEs and the DiHOMEs were also recently shown to have neutrophil chemotactic activity. We evaluated whether the neutrophil respiratory burst, a surge of oxidant production thought to play an important role in limiting certain bacterial and fungal infections, is modulated by members of the EpOME metabolic pathway. We present evidence that the DiHOMEs suppress the neutrophil respiratory burst by a mechanism distinct from that of respiratory burst inhibitors such as cyclosporin H or lipoxin A4, which inhibit multiple aspects of neutrophil activation.

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Direct cardiovascular actions of two metabolites of linoleic acid

Cited by 28 publications

References 10 publications

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

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

An oxidized derivative of linoleic acid affects aldosterone secretion by adrenal cells in vitro

Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

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