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Impact of hematopoietic cyclooxygenase-1 deficiency on obesity-linked adipose tissue inflammation and metabolic disorders in mice.
Saraswathi V, Ramnanan CJ, Wilks AW, Desouza CV, Eller AA, Murali G, Ramalingam R, Milne GL, Coate KC, Edgerton DS
(2013) Metabolism 62: 1673-85
MeSH Terms: Adiponectin, Adipose Tissue, Animals, Biomarkers, Blotting, Western, Bone Marrow Cells, Bone Marrow Transplantation, Cyclooxygenase 1, Diet, High-Fat, Eating, Female, Fluorescent Antibody Technique, Inflammation, Kidney, Leptin, Liver, Macrophages, Mice, Mice, Knockout, Obesity, Real-Time Polymerase Chain Reaction, Weight Gain
Show Abstract · Added March 26, 2014
OBJECTIVE - Adipose tissue (AT)-specific inflammation is considered to mediate the pathological consequences of obesity and macrophages are known to activate inflammatory pathways in obese AT. Because cyclooxygenases play a central role in regulating the inflammatory processes, we sought to determine the role of hematopoietic cyclooxygenase-1 (COX-1) in modulating AT inflammation in obesity.
MATERIALS/METHODS - Bone marrow transplantation was performed to delete COX-1 in hematopoietic cells. Briefly, female wild type (wt) mice were lethally irradiated and injected with bone marrow (BM) cells collected from wild type (COX-1+/+) or COX-1 knock-out (COX-1-/-) donor mice. The mice were fed a high fat diet for 16 weeks.
RESULTS - The mice that received COX-1-/- bone marrow (BM-COX-1-/-) exhibited a significant increase in fasting glucose, total cholesterol and triglycerides in the circulation compared to control (BM-COX-1+/+) mice. Markers of AT-inflammation were increased and were associated with increased leptin and decreased adiponectin in plasma. Hepatic inflammation was reduced with a concomitant reduction in TXB2 levels. The hepatic mRNA expression of genes involved in lipogenesis and lipid transport was increased while expression of genes involved in regulating hepatic glucose output was reduced in BM-COX-1-/- mice. Finally, renal inflammation and markers of renal glucose release were increased in BM-COX-1-/- mice.
CONCLUSION - Hematopoietic COX-1 deletion results in impairments in metabolic homeostasis which may be partly due to increased AT inflammation and dysregulated adipokine profile. An increase in renal glucose release and hepatic lipogenesis/lipid transport may also play a role, at least in part, in mediating hyperglycemia and dyslipidemia, respectively.
Published by Elsevier Inc.
2 Communities
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22 MeSH Terms
Human platelets generate phospholipid-esterified prostaglandins via cyclooxygenase-1 that are inhibited by low dose aspirin supplementation.
Aldrovandi M, Hammond VJ, Podmore H, Hornshaw M, Clark SR, Marnett LJ, Slatter DA, Murphy RC, Collins PW, O'Donnell VB
(2013) J Lipid Res 54: 3085-97
MeSH Terms: Aspirin, Blood Platelets, Calcium, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Dinoprostone, Dose-Response Relationship, Drug, Esterification, Feedback, Physiological, Humans, Intracellular Space, MAP Kinase Kinase 1, Phosphatidylethanolamines, Phospholipids, Platelet Activation, Prostaglandin D2, Prostaglandins, Protein Kinase C, Receptor, PAR-1, Thrombin, src-Family Kinases
Show Abstract · Added March 7, 2014
Oxidized phospholipids (oxPLs) generated nonenzymatically display pleiotropic biological actions in inflammation. Their generation by cellular cyclooxygenases (COXs) is currently unknown. To determine whether platelets generate prostaglandin (PG)-containing oxPLs, then characterize their structures and mechanisms of formation, we applied precursor scanning-tandem mass spectrometry to lipid extracts of agonist-activated human platelets. Thrombin, collagen, or ionophore activation stimulated generation of families of PGs comprising PGE₂ and D₂ attached to four phosphatidylethanolamine (PE) phospholipids (16:0p/, 18:1p/, 18:0p/, and 18:0a/). They formed within 2 to 5 min of activation in a calcium, phospholipase C, p38 MAP kinases, MEK1, cPLA₂, and src tyrosine kinase-dependent manner (28.1 ± 2.3 pg/2 × 10⁸ platelets). Unlike free PGs, they remained cell associated, suggesting an autocrine mode of action. Their generation was inhibited by in vivo aspirin supplementation (75 mg/day) or in vitro COX-1 blockade. Inhibitors of fatty acyl reesterification blocked generation significantly, while purified COX-1 was unable to directly oxidize PE in vitro. This indicates that they form in platelets via rapid esterification of COX-1 derived PGE₂/D₂ into PE. In summary, COX-1 in human platelets acutely mediates membrane phospholipid oxidation via formation of PG-esterified PLs in response to pathophysiological agonists.
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21 MeSH Terms
12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.
Yeung J, Apopa PL, Vesci J, Stolla M, Rai G, Simeonov A, Jadhav A, Fernandez-Perez P, Maloney DJ, Boutaud O, Holman TR, Holinstat M
(2013) Thromb Haemost 110: 569-81
MeSH Terms: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid, Animals, Arachidonate 12-Lipoxygenase, Blood Platelets, Cyclooxygenase 1, Eicosanoids, Flow Cytometry, Humans, Mice, Mice, Transgenic, Platelet Activation, Platelet Adhesiveness, Platelet Aggregation, Platelet Membrane Glycoproteins, Receptors, Thrombin, Thrombosis, Time Factors
Show Abstract · Added March 27, 2014
Following initial platelet activation, arachidonic acid is metabolised by cyclooxygenase-1 and 12-lipoxygenase (12-LOX). While the role of 12-LOX in the platelet is not well defined, recent evidence suggests that it may be important for regulation of platelet activity and is agonist-specific in the manner in which it regulates platelet function. Using small molecule inhibitors selective for 12-LOX and 12-LOX-deficient mice, the role of 12-LOX in regulation of human platelet activation and thrombosis was investigated. Pharmacologically inhibiting 12-LOX resulted in attenuation of platelet aggregation, selective inhibition of dense versus alpha granule secretion, and inhibition of platelet adhesion under flow for PAR4 and collagen. Additionally, 12-LOX-deficient mice showed attenuated integrin activity to PAR4-AP and convulxin compared to wild-type mice. Finally, platelet activation by PARs was shown to be differentially dependent on COX-1 and 12-LOX with PAR1 relying on COX-1 oxidation of arachidonic acid while PAR4 being more dependent on 12-LOX for normal platelet function. These studies demonstrate an important role for 12-LOX in regulating platelet activation and thrombosis. Furthermore, the data presented here provide a basis for potentially targeting 12-LOX as a means to attenuate unwanted platelet activation and clot formation.
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17 MeSH Terms
2-Carbaborane-3-phenyl-1H-indoles--synthesis via McMurry reaction and cyclooxygenase (COX) inhibition activity.
Laube M, Neumann W, Scholz M, Lönnecke P, Crews B, Marnett LJ, Pietzsch J, Kniess T, Hey-Hawkins E
(2013) ChemMedChem 8: 329-35
MeSH Terms: Animals, Boron Compounds, Cyclization, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Indoles, Mice, Models, Molecular, Sheep
Show Abstract · Added June 1, 2014
Cyclooxygenase-2 (COX-2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX-2-selective 2,3-disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2-carbaborane-3-phenyl-1H-indoles could be synthesized by McMurry cyclization of the corresponding amides. Whereas the meta-carbaboranyl-substituted derivatives lacked COX inhibitory activity, an ortho-carbaboranyl analogue was active, but showed a selectivity shift toward COX-1.
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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10 MeSH Terms
Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma.
Sahasrabuddhe VV, Gunja MZ, Graubard BI, Trabert B, Schwartz LM, Park Y, Hollenbeck AR, Freedman ND, McGlynn KA
(2012) J Natl Cancer Inst 104: 1808-14
MeSH Terms: Aged, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Carcinoma, Hepatocellular, Chronic Disease, Comorbidity, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Female, Humans, Incidence, Liver Diseases, Liver Neoplasms, Male, Middle Aged, Odds Ratio, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, United States
Show Abstract · Added March 5, 2014
BACKGROUND - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.
METHODS - We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health-AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.
RESULTS - Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.
CONCLUSIONS - Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.
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22 MeSH Terms
Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system.
Kirkby NS, Lundberg MH, Harrington LS, Leadbeater PD, Milne GL, Potter CM, Al-Yamani M, Adeyemi O, Warner TD, Mitchell JA
(2012) Proc Natl Acad Sci U S A 109: 17597-602
MeSH Terms: Animals, Blotting, Western, Cardiovascular System, Cells, Cultured, Cyclooxygenase 1, Cyclooxygenase 2, Endothelium, Vascular, Epoprostenol, Humans, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout
Show Abstract · Added March 26, 2014
Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
1 Communities
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13 MeSH Terms
Prostaglandin H synthase-2-catalyzed oxygenation of 2-arachidonoylglycerol is more sensitive to peroxide tone than oxygenation of arachidonic acid.
Musee J, Marnett LJ
(2012) J Biol Chem 287: 37383-94
MeSH Terms: Amino Acid Substitution, Animals, Arachidonic Acid, Arachidonic Acids, Benzothiazoles, Biocatalysis, Cattle, Chromogenic Compounds, Cyclooxygenase 1, Cyclooxygenase 2, Endocannabinoids, Enzyme Activation, Gene Knockdown Techniques, Glutathione Peroxidase, Glycerides, Humans, Kinetics, Mice, NIH 3T3 Cells, Oxidation-Reduction, Oxidative Stress, Peroxides, Phospholipid Hydroperoxide Glutathione Peroxidase, Prostaglandins, RNA Interference, Sulfonic Acids
Show Abstract · Added March 7, 2014
The endocannabinoid, 2-arachidonoylglycerol (2-AG), is a selective substrate for the inducible isoform of prostaglandin H synthase (PGHS), PGHS-2. Its turnover leads to the formation of glyceryl esters of prostaglandins (PG-Gs), a subset of which elicits agonism at unique, as yet unidentified, receptors. The k(cat)/K(m) values for oxygenation of arachidonic acid (AA) and 2-AG by PGHS-2 are very similar, but the sensitivities of the two substrates to peroxide-dependent activation have not been compared. 15-Hydroperoxy derivatives of AA and 2-AG were found to be comparable in their ability to serve as substrates for the peroxidase activities of PGHS-2, PGHS-1, and glutathione peroxidase (GPx). They also were comparable in the activation of AA oxygenation by cyanide-inhibited PGHS-2. However, oxygenation of 2-AG was significantly suppressed relative to AA by the presence of GPx and GSH. Furthermore, 2-AG oxygenation by peroxidase-deficient H388YmPGHS-2 was much less efficient than AA oxygenation. Wild-type rates of 2-AG oxygenation were restored by treatment of H388YmPGHS-2 with hydroperoxide derivatives of AA or 2-AG. RNAi silencing of phospholipid hydroperoxide-specific GPx (GPx4) in NIH/3T3 cells led to increases in cellular peroxidation and in the levels of the isoprostane product, 8-epi-PGF(2α). GPx4 silencing led to 2-4-fold increases in PG-G formation but no change in PG formation. Thus, cellular peroxide tone may be an important determinant of the extent of endocannabinoid oxygenation by PGHS-2.
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26 MeSH Terms
Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages.
Chen X, Barozzi I, Termanini A, Prosperini E, Recchiuti A, Dalli J, Mietton F, Matteoli G, Hiebert S, Natoli G
(2012) Proc Natl Acad Sci U S A 109: E2865-74
MeSH Terms: Animals, Base Sequence, Chromatin Immunoprecipitation, Cyclooxygenase 1, Cytokines, DNA Primers, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Expression Regulation, Genomics, Histone Deacetylases, Macrophages, Membrane Proteins, Mice, Mice, Transgenic, Molecular Sequence Data, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA
Show Abstract · Added March 26, 2014
Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic approach, we found that Hdac3-deficient macrophages were unable to activate almost half of the inflammatory gene expression program when stimulated with LPS. A large part of the activation defect was attributable to loss of basal and LPS-inducible expression of IFN-β, which maintains Stat1 protein levels in unstimulated cells and acts in an autocrine/paracrine manner after stimulation to promote a secondary wave of Stat1-dependent gene expression. Loss of Hdac3-mediated repression of nuclear receptors led to hyperacetylation of thousands of genomic sites and associated gene derepression. The up-regulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), a nuclear receptor target, had a causative role in the phenotype because its chemical inhibition reverted, albeit partially, the Ifn-β activation defect. These data indicate a central role for Hdac3 in inflammation and may have relevance for the use of selective Hdac inhibitors as antiinflammatory agents.
2 Communities
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19 MeSH Terms
Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.
Tanaka K, Furuyashiki T, Kitaoka S, Senzai Y, Imoto Y, Segi-Nishida E, Deguchi Y, Breyer RM, Breyer MD, Narumiya S
(2012) J Neurosci 32: 4319-29
MeSH Terms: 3,4-Dihydroxyphenylacetic Acid, Analysis of Variance, Animals, Benzazepines, Calcium-Binding Proteins, Corticosterone, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Dinoprostone, Disease Models, Animal, Disease Susceptibility, Dominance-Subordination, Dopamine, Dopamine Antagonists, Homovanillic Acid, Interpersonal Relations, Maze Learning, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Microfilament Proteins, Neural Pathways, Oxidopamine, Prefrontal Cortex, Pyrazoles, Receptors, Prostaglandin E, Signal Transduction, Stress, Psychological, Sulfonamides, Time Factors, Tyrosine 3-Monooxygenase, Ventral Tegmental Area
Show Abstract · Added December 21, 2013
Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E(2) (PGE(2)), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE(2) level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.
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35 MeSH Terms
Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome.
Smith JP, Haddad EV, Taylor MB, Oram D, Blakemore D, Chen Q, Boutaud O, Oates JA
(2012) Hypertension 59: 719-25
MeSH Terms: Aged, Aspirin, Blood Platelets, Cardiovascular Diseases, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Gas Chromatography-Mass Spectrometry, Humans, Male, Metabolic Syndrome, Middle Aged, Platelet Aggregation, Prospective Studies, Thromboxane B2, Treatment Outcome
Show Abstract · Added March 27, 2014
Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin (81 mg) on platelet COX-1 in 135 patients with stable coronary artery disease by measuring serum thromboxane B(2) (sTxB(2)) as an indicator of inhibition of platelet COX-1. A nested randomized study compared enteric-coated with immediate-release formulations of aspirin. We found that sTxB(2) was systematically higher among the 83 patients with metabolic syndrome than among the 52 patients without (median: 4.0 versus 3.02 ng/mL; P=0.013). Twelve patients (14%) with metabolic syndrome, but none without metabolic syndrome, had sTxB(2) levels consistent with inadequate inhibition of COX (sTxB(2) ≥13 ng/mL). In linear regression models, metabolic syndrome (but none of its individual components) significantly associated with higher levels of log-transformed sTxB(2) (P=0.006). Higher levels of sTxB(2) associated with greater residual platelet function measured by aggregometry-based methods. Among the randomized subset, sTxB(2) levels were systematically higher among patients receiving enteric-coated aspirin. Last, urinary 11-dehydro thromboxane B(2) did not correlate with sTxB(2), suggesting that the former should not be used to quantitate aspirin's pharmacological effect on platelets. In conclusion, metabolic syndrome, which places patients at high risk for thrombotic cardiovascular events, strongly and uniquely associates with less effective inhibition of platelet COX-1 by aspirin.
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18 MeSH Terms