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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2009-5-21
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pubmed:abstractText |
Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) increase the incidence of cardiovascular and cerebrovascular events. Complete disruption of the murine gene encoding COX-2 (Ptgs2) leads to renal developmental problems, as well as female reproductive anomalies and patent ductus arteriosus of variable penetrance in newborns, thus rendering this genetic approach difficult to compare with coxib administration. Here, we created hypomorphic Ptgs2 (COX-2(Neo/Neo)) mice in which COX-2 expression is suppressed to an extent similar to that achieved with coxibs, but not eliminated, in an attempt to circumvent these difficulties. In LPS-challenged macrophages and cytokine-stimulated endothelial cells obtained from COX-2(Neo/Neo) mice, COX-2 expression was reduced 70-90%, and these mice developed a mild renal phenotype compared with COX-2 mice possessing an active site mutation (COX-2(Y385F/Y385F)), with minimal signs of renal dysfunction as measured by FITC-inulin clearance and blood urea nitrogen. These COX-2 knockdown mice displayed an increased propensity for thrombogenesis compared with their wild-type (COX-2(+/+)) littermates observed by intravital microscopy in cremaster muscle arterioles upon ferric chloride challenge. Measurement of urinary prostanoid metabolites indicated that COX-2(Neo/Neo) mice produced 50% less prostacyclin but similar levels of PGE(2) and thromboxane compared with COX-2(+/+) mice in the absence of any blood pressure and ex vivo platelet aggregation abnormalities. COX-2(Neo/Neo) mice, therefore, provide a genetic surrogate of coxib therapy with disrupted prostacyclin biosynthesis that predisposes to induced arterial thrombosis.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Chlorides,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/Dinoprostone,
http://linkedlifedata.com/resource/pubmed/chemical/Epoprostenol,
http://linkedlifedata.com/resource/pubmed/chemical/Ferric Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ptgs1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Ptgs2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Thromboxane B2,
http://linkedlifedata.com/resource/pubmed/chemical/ferric chloride
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0363-6119
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
296
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
R1751-60
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:19357295-Animals,
pubmed-meshheading:19357295-Blood Pressure,
pubmed-meshheading:19357295-Blood Urea Nitrogen,
pubmed-meshheading:19357295-Cardiovascular System,
pubmed-meshheading:19357295-Cells, Cultured,
pubmed-meshheading:19357295-Chlorides,
pubmed-meshheading:19357295-Cyclooxygenase 1,
pubmed-meshheading:19357295-Cyclooxygenase 2,
pubmed-meshheading:19357295-Cytokines,
pubmed-meshheading:19357295-Dinoprostone,
pubmed-meshheading:19357295-Disease Models, Animal,
pubmed-meshheading:19357295-Endothelial Cells,
pubmed-meshheading:19357295-Epoprostenol,
pubmed-meshheading:19357295-Ferric Compounds,
pubmed-meshheading:19357295-Glomerular Filtration Rate,
pubmed-meshheading:19357295-Heart Rate,
pubmed-meshheading:19357295-Kidney,
pubmed-meshheading:19357295-Macrophages, Peritoneal,
pubmed-meshheading:19357295-Membrane Proteins,
pubmed-meshheading:19357295-Mice,
pubmed-meshheading:19357295-Mice, Knockout,
pubmed-meshheading:19357295-Microscopy, Video,
pubmed-meshheading:19357295-Thrombosis,
pubmed-meshheading:19357295-Thromboxane B2,
pubmed-meshheading:19357295-Time Factors
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pubmed:year |
2009
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pubmed:articleTitle |
Renal and cardiovascular characterization of COX-2 knockdown mice.
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pubmed:affiliation |
Department of Physiology, Queen's University, Kingston, Ontario, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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