CYP-eicosanoids—A new link between omega-3 fatty acids and cardiac disease?

Westphal, Christina; Konkel, Anne; Schunck, Wolf‐Hagen

doi:10.1016/j.prostaglandins.2011.09.001

Cited by 103 publications

(90 citation statements)

References 112 publications

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“…In humans, CYP2J2 is highly expressed in cardiac myocytes and the endothelium of coronary arteries where it plays significant roles in cardiovascular diseases and inflammation. [4][5][6][7] This enzyme Abbreviations: CPR, cytochrome P450 reductase; CYP2J2, cytochrome P450 2J2; ND, Nanodiscs; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POPS, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 Additionally, CYP2J2 catalyzes the conversion of the omega-3 fatty acids into physiologically active products. 5 Both the omega-3 and omega-6 fatty acid metabolites are known dilators of the microvasculature and are essential for heart homeostatic equilibrium. 5,10 Recently, CYP2J2 has also been found to be relevant in both cancer and preeclampsia pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

“…5 Both the omega-3 and omega-6 fatty acid metabolites are known dilators of the microvasculature and are essential for heart homeostatic equilibrium. 5,10 Recently, CYP2J2 has also been found to be relevant in both cancer and preeclampsia pathophysiology. [11][12][13][14] EETs are recognized as major promoters of angiogenesis and consequently enhance tumor cell survival.…”

Section: Introductionmentioning

confidence: 99%

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Functional studies of N‐terminally modified CYP2J2 epoxygenase in model lipid bilayers

et al. 2013

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CYP2J2 epoxygenase is a membrane bound cytochrome P450 that converts omega-3 and omega-6 fatty acids into physiologically active epoxides. In this work, we present a comprehensive comparison of the effects of N-terminal modifications on the properties of CYP2J2 with respect to the activity of the protein in model lipid bilayers using Nanodiscs. We demonstrate that the complete truncation of the N-terminus changes the association of this protein with the E.coli membrane but does not disrupt incorporation in the lipid bilayers of Nanodiscs. Notably, the introduction of silent mutations at the N-terminus was used to express full length CYP2J2 in E. coli while maintaining wild-type functionality. We further show that lipid bilayers are essential for the productive use of NADPH for ebastine hydroxylation by CYP2J2. Taken together, it was determined that the presence of the N-terminus is not as critical as the presence of a membrane environment for efficient electron transfer from cytochrome P450 reductase to CYP2J2 for ebastine hydroxylation in Nanodiscs. This suggests that adopting the native-like conformation of CYP2J2 and cytochrome P450 reductase in lipid bilayers is essential for effective use of reducing equivalents from NADPH for ebastine hydroxylation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional studies of N‐terminally modified CYP2J2 epoxygenase in model lipid bilayers

et al. 2013

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“…In addition, lipid peroxide levels were enhanced in dietary vitamin E deficiency in the heart (16). AA is one of the diverse free fatty acids, that not only participates in myocardium energy supply, but AA and its CYP-derived metabolites may also act as secondary messenger molecules for protein kinases, including protein kinase C, mitogen-activated protein kinase, protein kinase A, Erk1/2, and Akt (13,17,18). AA is synthesized from linoleic acid, and previous studies have reported that dietary linoleic acid supplementation was beneficial to DCM patients.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of arachidonic acid by the cytochrome P450 enzyme in patients with chronic Keshan disease and dilated cardiomyopathy

Zhou

Wang

et al. 2015

Biomedical Reports

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Abstract. Keshan disease (KD) is an endemic cardiomyopathy. The etiology of KD is selenium deficiency; however, it is not the only one and there is no effective approach to preventing and curing this disease. The aim of the present study was to explore the differences in the role of arachidonic acid (AA) by the cytochrome P450 enzyme between chronic KD (CKD), dilated cardiomyopathy (DCM) and control patients. Reverse transcription-quantitative polymerase chain reaction was used to detect the CYP1A1 and CYP2C19 gene expression levels in 6 CKD patients, 6 DCM and 6 healthy controls. An enzyme-linked immunosorbent assay kit was applied to detect serum protein expression of CYP1A1 and CYP2C19, AA and epoxyeicosatrienoic acids (EETs), and 20-hydroxyeicosatetraenoic acids (20-HETE) in 67 CKD patients, 28 DCM, and 58 controls. The present results showed that the expression levels of CYP1A1 and CYP2C19 genes were significantly upregulated compared with the control group (P<0.01). The expression level of the CYP1A1 protein in the CKD (49.55±35.11 pg/ml) and DCM (46.68 ±13.01 pg/ml) groups were enhanced compared with the control group (44.33±16.76 pg/ml) (P<0.01). The production of the CYP2C19 protein in the CKD (57.52±28.22 pg/ml) and DCM (56.36±11.26 pg/ml) groups was enhanced compared with the control group (51.43±10.76 pg/ml). The concentrations of AA in the CKD (126.27±47.91 ng/ml) and DCM (133.24±58.67 ng/ml) groups were also significantly increased compared to the control (78.16±23.90 ng/ml) (P<0.001). The concentration of 20-HETE in the CKD (198.34±17.22 ng/ml) and DCM (194.46±20.35 ng/ml) groups were also significantly increased compared to the control (130.10±16.10 ng/ml) (P<0.001). The only difference between CKD and DCM was for the expression of the CYP1A1 gene and protein.The maximum concentration of EETs was in the control group (44.37±6.14 pg/ml), and the other two groups were lower than the control group (P<0.001). These findings indicated that AA-derived CYP450 metabolites may have a critical role in the pathogenesis of KD and DCM. Upregulation of the CYP2C19 gene and frequent protein expression may be a protective compensation reaction, while CYP1A1 may aggravate myocardial injury.

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“…In addition to AA, CYP2J2 can also metabolise the structurally related linoleic, docosahexaenoic and eicosapentaenoic acids to epoxy-products with biological activity [7,8].…”

Section: Introductionmentioning

confidence: 99%

Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2

et al. 2016

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CYP-eicosanoids—A new link between omega-3 fatty acids and cardiac disease?

Cited by 103 publications

References 112 publications

Functional studies of N‐terminally modified CYP2J2 epoxygenase in model lipid bilayers

Functional studies of N‐terminally modified CYP2J2 epoxygenase in model lipid bilayers

Metabolism of arachidonic acid by the cytochrome P450 enzyme in patients with chronic Keshan disease and dilated cardiomyopathy

Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2

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