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

Edin, Matthew L.; Wang, Zhong Jing; Bradbury, J. Alyce; Graves, Joan P.; Lih, Fred B.; DeGraff, Laura M.; Foley, Julie F.; Torphy, Robert J.; Rønnekleiv, Oline K.; Tomer, Kenneth B.; Lee, Craig; Zeldin, Darryl C.

doi:10.1096/fj.11-188300

Cited by 105 publications

(133 citation statements)

References 55 publications

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“…In contrast, COX-and LOX-derived metabolites are unaffected in these mice (20). To characterize the impact of reduced endothelial EETs, we also generated a unique murine model with endothelial expression of human sEH (Tie2-sEH-Tr) (22). ECs isolated from these mice have significantly decreased EET levels relative to ECs isolated from WT mice (20).…”

Section: Resultsmentioning

confidence: 99%

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Epoxyeicosanoids promote organ and tissue regeneration

Panigrahy

Kalish

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

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Section: Resultsmentioning

confidence: 99%

“…ECs were isolated from WT, Tie2-CYP2J2-Tr, Tie2-CYP2C8-Tr, and Tie2-sEH-Tr mice, and LC-MS/MS analysis was performed as described (19,20,22). All human studies were reviewed and approved by the Institutional Review Board at Lahey Clinic Medical Center.…”

Section: Methodsmentioning

confidence: 99%

Epoxyeicosanoids promote organ and tissue regeneration

Panigrahy

Kalish

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Negative ion electrospray ionization tandem mass spectrometry was used for detection. Analyses were performed on an MDS Sciex API 3000 equipped with a TurboIonSpray source (Applied Biosystems, Foster City, CA) (28).…”

Section: Extraction and Analysis Of Media And Cellular Eicosanoids-mentioning

confidence: 99%

“…Incubating INS 832/13 Cells with Polyunsaturated Fatty Acid (PUFA) Reduced Both Acsl4 Expression and GSIS-Chronic exposure of INS 832/13 cells to exogenous FA reduces GSIS (28). To determine the effect of FA on Acsl4 expression, we incubated INS 832/13 cells with 0.5-1 mM concentrations of either oleate:palmitate (2:1 unsaturated:saturated molar ratio) or oleate:palmitate:AA (6:3:1 molar ratio) for 72 h. AA was added to the oleate:palmitate incubation because PUFAs are present in the typical Western diet and associated with meta- bolic disease (38).…”

Section: Eets Inhibit Gsis and Inhibiting Eet Actions Rescue The Redumentioning

confidence: 99%

Diminished Acyl-CoA Synthetase Isoform 4 Activity in INS 832/13 Cells Reduces Cellular Epoxyeicosatrienoic Acid Levels and Results in Impaired Glucose-stimulated Insulin Secretion

Klett

Chen

Edin

et al. 2013

Journal of Biological Chemistry

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Background:The role of intracellular lipid metabolism as it relates to nutrient-coupled glucose-stimulated insulin secretion has not been fully elucidated. Results: Knockdown of acyl-CoA synthetase isoform 4 impairs glucose-stimulated insulin secretion caused by decreased cellular epoxyeicosatrienoic acids. Conclusion: Acyl-CoA synthetase 4 is required for optimal glucose-stimulated insulin secretion. Significance: Understanding the role of beta-cell lipid metabolism is needed to develop novel strategies to enhance insulin secretion.

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“…Among the human counterparts of CYP-13A12, CYP2J2 has attracted particular interest for its protective role in ischemia/reperfusion injury. CYP2J2 overexpression in transgenic mice mediates improved postischemic functional recovery of the heart and reduces infarction size [34,35]. CYP2J2 overexpression also protects against hypoxia-reoxygenation injury in cultured endothelial cells [36].…”

Section: Discussionmentioning

confidence: 99%

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Keller

Ellieva

Dengke

et al. 2014

Biochemical Journal

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SHORT TITLE:CYP-13A12 of C. elegans is a PUFA-epoxygenase 4 SYNOPSISA specific behavioural response of Caenorhabditis elegans, the rapid increase of locomotion in response to anoxia/reoxygenation called the O2-ON response, has been used to model key aspects of ischemia/reperfusion injury. A genetic suppressor screen demonstrated a direct causal role of CYP-13A12 in this response and suggested that CYP-eicosanoids, which in mammals influence the contractility of cardiomyocytes and vascular smooth muscle cells, might function in C. elegans as specific regulators of the body muscle cell activity. Here we show that co-expression of CYP-13A12 with the NADPH-CYP-reductase EMB-8 in insect cells resulted in the reconstitution of an active microsomal monooxygenase system that metabolised EPA (eicosapentaenoic acid) and also AA (arachidonic acid) to specific sets of regioisomeric epoxy and hydroxy derivatives. Main products included 17,18-EEQ (epoxyeicosatetraenoic acid) from EPA and 14,15-EET (epoxyeicosatrienoic acid) from AA. Locomotion assays showed that the defective O2-ON response of C20-PUFA-deficient, ∆ -12 and ∆ -6 fatty acid desaturase mutants (fat-2 and fat-3, respectively) can be restored by feeding the nematodes AA or EPA, but not ETYA (eicosatetraynoic acid), a non-metabolisable AAanalogue. Already short-term incubation with 17,18-EEQ was sufficient to rescue the impaired locomotion of the fat-3 strain. The endogenous level of free 17,18-EEQ declined during anoxia and was rapidly restored in response to reoxygenation. Based on these results, we suggest that CYP-dependent eicosanoids such as 17,18-EEQ function as signalling molecules in the regulation of the O2-ON response in C. elegans. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity already under normoxic conditions and was effective not only with C20-PUFA mutants but to a lesser extent also with wild-type worms. KEYWORDS:Eicosanoids; Polyunsaturated fatty acids; Caenorhabditis elegans; Cytochrome P450; Reoxygenation; 17,18-EEQ ABBREVIATIONS USED: AA, arachidonic acid; CID, collision-induced dissociation; COD, carbon monoxide difference; CPR, NADPH-CYP reductase; CYP, cytochrome P450; DiHETE, dihydroxyeicosatetraenoic acid; DTT, dithiothreitol; EGL, egg laying defect; EGLN, EGL nine; EEQ, epoxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; ETYA, eicosatetraynoic acid; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; HEET, hydroxyepoxyeicosatrienoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HIF, hypoxia inducible factor; LC, liquid chromatography; MC, pharyngeal marginal cell; MS, mass spectrometry; NGM, nematode growth medium; PUFA, polyunsaturated fatty acid; RP, reversed-phase 5 INTRODUCTIONOxygen deprivation upon restriction of blood supply followed by reperfusion and concomitant reoxygenation causes tissue injury and is involved in the initiation of various human pathologies including ischemic stroke, myocardial infarction, and ac...

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

Cited by 105 publications

References 55 publications

Epoxyeicosanoids promote organ and tissue regeneration

Epoxyeicosanoids promote organ and tissue regeneration

Diminished Acyl-CoA Synthetase Isoform 4 Activity in INS 832/13 Cells Reduces Cellular Epoxyeicosatrienoic Acid Levels and Results in Impaired Glucose-stimulated Insulin Secretion

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

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