Document Detail


COX-1(+/-)COX-2(-/-) genotype in mice is associated with shortened time to carotid artery occlusion through increased PAI-1.
MedLine Citation:
PMID:  21138526     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: We found a high incidence of thrombotic deaths in COX-1(+/-)COX-2(-/-) mice and sought to define the mechanism of these events. The cyclooxygenase products thromboxane A(2) and prostacyclin are important in the regulation of coagulation but their role in fibrinolysis is largely unexplored. PAI-1 blocks fibrinolysis by inhibiting plasminogen activator.
AIM: Our objective was to explain the mechanism of increased thrombosis associated with the COX-1(+/-)COX-2(-/-) genotype.
METHODS: Carotid artery occlusion times were measured after photochemical injury. PAI-1 levels were measured in the plasma by ELISA. PAI-1 levels in the aorta were measured by RT-PCR and Western blotting. Urinary metabolites of Thromboxane A(2) and prostacyclin were measured by ELISA.
RESULTS: The COX-1(+/-)COX-2(-/-) genotype is associated with a decreased time to occlusion in the carotid artery thrombosis model (30 ± 5 minutes vs 60 ± minutes in wild type, p<.001). The COX-1(-/-)COX-2(+/+), COX-1(+/-)COX-2(+/-) and COX-1(+/-)COX-2(+/+) all had occlusion times similar to wild type. COX-1(+/+)COX-2(-/-) had a prolonged occlusion time. COX-1(+/-)COX-2(-/-) had increased PAI-1 levels in the plasma and aorta and with a prolonged euglobulin lysis time (37.4 ± 10.2 hours vs 15.6 ± 9.8 hours in wild type, p<.004). The decreased time to occlusion in the COX-1(+/-)COX2(-/-) mice was normalized by an inhibitory antibody to PAI-1 whereas the antibody had no effect on the time to occlusion in wild type mice.
CONCLUSION: The COX-1(+/-)COX-2(-/-) genotype is associated with a shortened time to occlusion in the carotid thrombosis model and the shortened time to occlusion is mediated through increased PAI-1 levels resulting in decreased fibrinolysis.
Authors:
T E Riehl; L He; L Zheng; S Greco; D M Tollefsen; W F Stenson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  9     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-28     Completed Date:  2011-06-02     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  350-60     Citation Subset:  IM    
Copyright Information:
© 2011 International Society on Thrombosis and Haemostasis.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carotid Stenosis / genetics*,  metabolism
Cyclooxygenase 1 / genetics*
Cyclooxygenase 2 / genetics*
DNA Primers
Disease Models, Animal
Female
Fibrinolysis
Genotype
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Plasminogen Activator Inhibitor 1 / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
DK33165/DK/NIDDK NIH HHS; DK55753/DK/NIDDK NIH HHS; HL55520/HL/NHLBI NIH HHS; R01 DK033165/DK/NIDDK NIH HHS; R01 DK033165-22/DK/NIDDK NIH HHS; R01 DK055753/DK/NIDDK NIH HHS; R01 DK055753-13/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Plasminogen Activator Inhibitor 1; EC 1.14.99.1/Cyclooxygenase 1; EC 1.14.99.1/Cyclooxygenase 2
Comments/Corrections

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