20-Hydroxyeicosatetraenoic acid is a potent dilator of mouse basilar artery: role of cyclooxygenase

2006 ◽  
Vol 291 (5) ◽  
pp. H2301-H2307 ◽  
Author(s):  
Xiang Fang ◽  
Frank M. Faraci ◽  
Terry L. Kaduce ◽  
Shawn Harmon ◽  
Mary L. Modrick ◽  
...  
Keyword(s):  
Basilar Artery ◽  
Brain Endothelial Cells ◽  
Epoxyeicosatrienoic Acid ◽  
Hydroxyeicosatetraenoic Acid ◽  
Mouse Brain Endothelial Cells ◽  
Endogenous Prostaglandins ◽  
Cytochrome P 450 ◽  
Dependent Mechanism

20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid (AA) metabolite synthesized by cytochrome P-450 ω-oxidases, is reported to produce vasoconstriction in the cerebral circulation. However, we find that like 14,15-epoxyeicosatrienoic acid (14,15-EET), 20-HETE produces dilation of mouse basilar artery preconstricted with U-46619 in vitro. Indomethacin inhibited the vasodilation produced by 20-HETE but not by 14,15-EET, suggesting a cyclooxygenase (COX)-dependent mechanism. Metabolic studies indicated several mechanisms that may play a role in this process. Mouse brain endothelial cells (MBEC) converted 20-HETE to 20-OH-PGE2, which was as potent as PGE2 in dilating the basilar artery. 20-HETE also stimulated AA release and PGE2 and 6-keto-PGF1α production in MBEC. Furthermore, the basilar artery converted 20-HETE to 20-COOH-AA, which also produced COX-dependent dilation of the basilar artery. 20-COOH-AA increased AA release and PGE2 and 6-keto-PGF1α production by the MBEC, but to a lesser extent than 20-HETE. Whereas the conversion of 20-HETE to 20-OH-PGE2 and production of endogenous prostaglandins probably are primarily responsible for vasodilation, the production of 20-COOH-AA also may contribute to this process.

scholarly journals Spleen Tyrosine Kinase Inhibition Modulates p53 Activity

2017 ◽  
Vol 10 ◽  
pp. 117906601773156 ◽  
Author(s):  
Mohammad Althubiti
Keyword(s):  
Tyrosine Kinase ◽  
Survival Rates ◽  
Lymphocytic Leukemia ◽  
Spleen Tyrosine Kinase ◽  
Ht1080 Cell ◽  
P53 Expression ◽  
Chemical Inhibitors ◽  
Dependent Mechanism

Spleen tyrosine kinase (SYK) is a cytoplasmic enzyme that promotes survival and proliferation of B cells. SYK inhibition has shown promising results in the treatment of arthritis and chronic lymphocytic leukemia (CLL). However, in other context, it has been shown that SYK overexpression in epithelial cancer cells induced senescence in p53-dependent mechanism, which underscored its antineoplastic activity in vitro. Here, we show that SYK was induced in response of DNA damage in parallel with p53 levels. In addition, using chemical inhibitors of SYK reduced p53 levels in HCT116 and HT1080 cell lines, which underlines the role of SYK inhibition on p53 activity. Furthermore, SYK inhibition modulated the cell growth, which resulted in a decreasing in cell death. Interestingly, SYK expression showed a positive prognosis in patients with solid tumors in correlations with their survival rates, as expected negative correlation was seen between SYK expression and survival rate of patients with CLL. In conclusion, these findings demonstrate that SYK inhibition modulates p53 expression and activity in HCT116 and HT1080 cells. Reconsidering using of SYK inhibitors in clinical setting in the future should be evaluated carefully in accordance with these findings to prevent the formation of secondary malignancies.

Cerebral microvascular endothelial cell tube formation: role of astrocytic epoxyeicosatrienoic acid release

2000 ◽  
Vol 278 (4) ◽  
pp. H1163-H1167 ◽  
Author(s):  
Diane H. Munzenmaier ◽  
David R. Harder
Keyword(s):  
Thymidine Incorporation ◽  
Tube Formation ◽  
Microvascular Endothelial Cell ◽  
Epoxyeicosatrienoic Acids ◽  
Epoxyeicosatrienoic Acid ◽  
Acid Release ◽  
Microvascular Endothelial ◽  
Cytochrome P 450 ◽  
The Brain

Cerebral microvascular endothelial cells (CMVEC) form tubes when cocultured with astrocytes (AS). Therefore, it appears that AS may be important in mediating angiogenesis in the brain. We hypothesized that AS modulate CMVEC tube formation by releasing a soluble factor. Thymidine incorporation in cultured CMVEC increased 305% when incubated with 50% conditioned AS medium for 24 h [control: 52,755 ± 4,838 counts per minute (cpm) per well, conditioned 161,082 ± 12,099 cpm/well, n = 8]. Because our laboratory has previously shown that AS can produce epoxyeicosatrienoic acids (EETs), which are known mitogens, we investigated whether release of EETs by AS is responsible for tube formation in the CMVEC-AS coculture. AS were seeded on Lab-Tek slides, CMVEC were seeded on the AS the next day, and cultures were allowed to progress for another 5 days with and without cytochrome P-450 epoxygenase blockade by 17-octadecynoic acid (17-ODYA). Tube formation in cocultures receiving 17-ODYA was significantly inhibited compared with control (93.8%). These data suggest that tube formation requires the release of EETs by AS.

Cytochrome P-450 and Peroxidase Oxidize Detoxication Products of Carcinogenic Aristolochic Acids (Aristolactams) to Reactive Metabolites Binding to DNA in vitro

1995 ◽  
Vol 60 (12) ◽  
pp. 2189-2199 ◽  
Author(s):  
Marie Stiborová ◽  
Eva Frei ◽  
Heinz H. Schmeiser ◽  
Manfred Wiessler
Keyword(s):  
Dna Adducts ◽  
Microsomal Cytochrome ◽  
Aristolochic Acids ◽  
Nuclease P1 ◽  
Order Of Magnitude ◽  
Prostaglandin H ◽  
Cytochrome P 450

We report the analysis of DNA adducts formed from aristolactams I and II, which are the final metabolites derived from carcinogenic aristolochic acids in vivo, after their oxidation by microsomal cytochrome P-450 and horseradish peroxidase in vitro. DNA adducts were detected and quantified using the nuclease P1-enhanced variation of the 32P-postlabeling assay. Quantitative analysis revelead that the extent of modification of DNA by aristolactams activated by peroxidase was more than one order of magnitude higher than for activation by microsomal cytochrome P-450. Peroxidase catalyzes the formation of active oxygen in the presence of NADH, H2O2 and aristolactams. Aristolactams are also oxidized by mammalian peroxidase prostaglandin H synthase. The possible role of aristolactams in carcinogenesis induced by aristolochic acid is discussed.

Decreased endothelium-dependent relaxation in subarachnoid hemorrhage-induced vasospasm: role of ET-1

1995 ◽  
Vol 269 (3) ◽  
pp. H1009-H1015 ◽  
Author(s):  
M. Zuccarello ◽  
A. Romano ◽  
M. Passalacqua ◽  
R. M. Rapoport
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Receptor Antagonist ◽  
Basilar Artery ◽  
Arterial Blood ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Endothelium Dependent Relaxation

The purpose of this study was to test whether endothelium-dependent relaxation is decreased during acute vasospasm following subarachnoid hemorrhage (SAH) and the mechanism underlying the decrease. Basilar artery in situ was 35% constricted 3 days following injection of autologous arterial blood into the rabbit cisterna magna compared with vessels from control rabbits. In situ suffusion with the endothelium-dependent relaxant, acetylcholine (ACh; 10 microM), relaxed resting and serotonin (5-HT)-contracted control vessels but not vasospastic and 5-HT-contracted vasospastic vessels. In contrast, the relaxant potency and efficacy of ACh was similar in control and vasospastic vessels contracted with 5-HT in vitro. In situ suffusion with the ETA-receptor antagonist, BQ-123 (1 microM), reversed the vasospasm by 51% and restored the magnitude of ACh relaxation of vasospastic and 5-HT-contracted vasospastic vessels to that of controls. ACh in situ and in vitro relaxed endothelin-1 (ET-1)-contracted control vessels to a smaller magnitude than 5-HT-contracted control vessels. These results suggest, in contrast to previous studies, that endothelium-dependent relaxation is decreased during acute vasospasm following SAH. The decreased endothelium-dependent relaxation is secondary to the underlying ET-1-mediated spasm. The inhibition of endothelium-dependent relaxation observed in situ following SAH cannot be demonstrated in vitro, presumably due to loss of the ET-1-mediated vasospasm.

Measuring antigen presentation in mouse brain endothelial cells ex vivo and in vitro

2015 ◽  
Vol 10 (12) ◽  
pp. 2016-2026 ◽  
Author(s):  
Shanshan W Howland ◽  
Sin Yee Gun ◽  
Carla Claser ◽  
Chek Meng Poh ◽  
Laurent Rénia
Keyword(s):  
Endothelial Cells ◽  
Antigen Presentation ◽  
Mouse Brain ◽  
Ex Vivo ◽  
Brain Endothelial Cells ◽  
Mouse Brain Endothelial Cells

scholarly journals The role of cytochrome P-450 in cholesterol biogenesis and catabolism

1972 ◽  
Vol 128 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Sandra D. Atkin ◽  
Eileen D. Palmer ◽  
P. D. English ◽  
B. Morgan ◽  
M. A. Cawthorne ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Carbon Disulphide ◽  
Normal Serum ◽  
Liver Cholesterol ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cytochrome P 450

1. Adjuvant-induced arthritis in rats is accompanied by a loss of activity of the drug-metabolizing enzyme system and a decrease in hepatic cytochrome P-450. 2. Arthritic rats have normal serum and liver cholesterol concentrations. 3. The rate of biogenesis of cholesterol in vivo and in vitro from either [14C]acetate or [14C]mevalonate in arthritic rats was the same as or greater than that found in control rats. 4. Treatment of rats with carbon disulphide (1ml/kg) resulted in a loss of drug-metabolizing-enzyme activity and increased cholesterol biogenesis. 5. The activity of cholesterol 7α-hydroxylase in adjuvant-induced arthritic rats did not differ significantly from that in control rats. 6. Rats fed with cholestyramine had an elevated hepatic cholesterol 7α-hydroxylase activity, but neither the concentration of cytochrome P-450 nor the activity of the drug-hydroxylating enzyme, aminopyrine demethylase, was affected. 7. The relationships between drug hydroxylation and cholesterol metabolism are discussed.

scholarly journals 20-HETE modulates myogenic response of skeletal muscle resistance arteries from hypertensive Dahl-SS rats

2001 ◽  
Vol 280 (3) ◽  
pp. H1066-H1074 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
Richard J. Roman ◽  
U. Murali Krishna ◽  
John R. Falck ◽  
Julian H. Lombard
Keyword(s):  
Skeletal Muscle ◽  
Arachidonic Acid ◽  
Dienoic Acid ◽  
Vessel Diameter ◽  
Transmural Pressure ◽  
Myogenic Response ◽  
Hydroxyeicosatetraenoic Acid ◽  
Resistance Arteries ◽  
Cytochrome P 450

The present study determined the role of 20-hydroxyeicosatetraenoic acid [20-HETE; produced by ω-hydroxylation of arachidonic acid via cytochrome P-450 (CP450) 4A enzymes] in regulating myogenic activation of skeletal muscle resistance arteries from normotensive (NT) and hypertensive (HT) Dahl salt-sensitive (SS) rats. Gracilis arteries (GA) were isolated from each rat and viewed via television microscopy, and changes in vessel diameter with altered transmural pressure were measured with a video micrometer. Under control conditions, GA from both groups exhibited strong, endothelium-independent myogenic activation. Treatment of GA with 17-octadecynoic acid (17-ODYA; inhibitor of CP450 4A enzymes) did not alter myogenic activation in NT rats, but impaired this response in HT animals. Treatment of GA from HT rats with dibromo-dodecynyl-methylsulfimide (DDMS; inhibitor of 20-HETE production) impaired myogenic activation, as did application of 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid, an antagonist for 20-HETE receptors. Application of iberiotoxin, a Ca2+-activated potassium (KCa) channel inhibitor, restored myogenic activation from HT rats treated with DDMS. These results suggest that myogenic activation of skeletal muscle resistance arteries from NT Dahl-SS rats does not depend on CP450, whereas myogenic activation of these vessels in HT Dahl-SS rats is partly a function of 20-HETE production, inhibiting KCachannels through a receptor-mediated process.

Role of cytochrome P-450 in endogenous antipyresis

2000 ◽  
Vol 279 (2) ◽  
pp. R455-R460 ◽  
Author(s):  
Wieslaw Kozak ◽  
Matthew J. Kluger ◽  
Anna Kozak ◽  
Maciej Wachulec ◽  
Karol Dokladny
Keyword(s):  
Arachidonic Acid ◽  
Intraperitoneal Administration ◽  
Dependent Manner ◽  
Epoxyeicosatrienoic Acid ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Rats And Mice ◽  
Dose Dependent ◽  
Cytochrome P 450

In previous reports, we (15, 18) and others (29) demonstrated data showing that various inhibitors of cytochrome P-450/epoxygenase augment fever in rats and mice, indicating that the enzyme may be involved in endogenous antipyresis. The aim of this study was to further test the hypothesis that the P-450-dependent epoxygenase pathway of arachidonic acid is part of the homeostatic system to control the height of fever. Sprague-Dawley rats were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide (LPS; 80 μg/kg). We demonstrate that intraperitoneal administration of P-450 inducers (bezafibrate and dehydroepiandrosterone, 10 and 100 mg/kg) before LPS reduced fever in rats in a dose-dependent manner. In complementary experiments, rats were implanted with brain cannulas in addition to the biotelemeters. Various isomers of epoxyeicosanoids were administered into the lateral ventricle at doses of 0.01 to 10 μg/rat to test their influence on LPS-induced fever in rats. Four of five isomers were antipyretic in a dose-dependent manner. The most potent antipyretic isomers were 11,12-epoxyeicosatrienoic acid (EET) followed by 14,15-EET, 8,9-EET, and 12(R) hydroxyeicosatetraenoic acid. These data support the hypothesis that the cytochrome P-450/epoxygenase pathway of arachidonate metabolism is part of the endogenous antipyretic system.

scholarly journals The epoxyeicosatrienoic acid analog PVPA ameliorates cyclosporine-induced hypertension and renal injury in rats

2016 ◽  
Vol 311 (3) ◽  
pp. F576-F585 ◽  
Author(s):  
Michael M. Yeboah ◽  
Md Abdul Hye Khan ◽  
Marla A. Chesnik ◽  
Amit Sharma ◽  
Mahesh P. Paudyal ◽  
...  
Keyword(s):  
Calcineurin Inhibitors ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Epoxyeicosatrienoic Acid ◽  
Patients At Risk ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Cytochrome P 450

The introduction of calcineurin inhibitors (CNI) into clinical practice in the late 1970s transformed organ transplantation and led to significant improvement in acute rejection episodes. However, despite their significant clinical utility, the use of these agents is hampered by the development of hypertension and nephrotoxicity, which ultimately lead to end-stage kidney disease and overt cardiovascular outcomes. There are currently no effective agents to treat or prevent these complications. Importantly, CNI-free immunosuppressive regimens lack the overall efficacy of CNI-based treatments and put patients at risk of allograft rejection. Cytochrome P-450 epoxygenase metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), have potent vasodilator and antihypertensive properties in addition to many cytoprotective effects, but their effects on CNI-induced nephrotoxicity have not been explored. Here, we show that PVPA, a novel, orally active analog of 14,15-EET, effectively prevents the development of hypertension and ameliorates kidney injury in cyclosporine-treated rats. PVPA treatment reduced proteinuria and renal dysfunction induced by cyclosporine. PVPA inhibited inflammatory cell infiltration into the kidney and decreased renal fibrosis. PVPA also reduced tubular epithelial cell apoptosis, attenuated the generation of reactive oxygen species, and modulated the unfolded protein response that is associated with endoplasmic reticulum stress. Consistent with the in vivo data, PVPA attenuated cyclosporine-induced apoptosis of NRK-52E cells in vitro. These data indicate that the cytochrome P-450/EET system offers a novel therapeutic strategy to treat or prevent CNI-induced nephrotoxicity.

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