Contribution of cyclooxygenase-1 to thromboxane formation, platelet-vessel wall interactions and atherosclerosis in the ApoE null mouse.
OBJECTIVE
Prostaglandin and thromboxane (TXA(2)) generation is increased in atherosclerosis. Studies with selective inhibitors attribute the enhanced prostacyclin (PGI(2)) generation to both cyclooxygenase-1 (COX-1) and COX-2 whereas the increased TXA(2) generation reflects platelet COX-1 expression. However, TXA(2) formation remains elevated in patients with cardiovascular disease on doses of aspirin that fully suppress platelet COX-1, suggesting other tissue sources for TXA(2) formation. Disruption of the thromboxane receptor gene suppresses the development of atherosclerosis. Notwithstanding this, the role of COX-1 in atherosclerosis is unclear, as it is widely distributed and contributes to a number of products, including those that potentially contribute to the resolution of inflammation.


RESULTS
We examined the role of COX-1 on prostaglandin generation, development of atherosclerosis and platelet-vessel wall interactions in the apoE(-/-) murine model by disrupting the COX-1 gene. ApoE(-/-)/COX-1(+/+), ApoE(-/-)/COX-1(+/-) and ApoE(-/-)/COX-1(-/-), were administered a 1% cholesterol diet for 8 weeks. Stable urinary metabolites of PGI(2) and TXA(2), which were markedly increased in the ApoE(-/-)/COX-1(+/+) were reduced by disruption of COX-1. Deletion of one or both copies of the COX-1 gene suppressed lesion formation. Assessment of platelet-vessel wall interactions by intravital microscopy showed a significant decrease in firm adhesion of platelets in the apoE/COX-1 double knockout (DKO).


CONCLUSIONS
COX-1 contributes to the enhanced formation of both PGI(2) and TXA(2) in atherosclerosis, and to the development of the disease. Non-platelet sources of COX-1 and TXA(2) that are inaccessible to standard doses of aspirin may contribute to the development of atherosclerosis.
McClelland
Sarah
S
UCD Conway Institute, University College Dublin, Ireland.
Gawaz
Meinrad
M
Kennerknecht
Elisabeth
E
Konrad
Carolin Sophie Ildiko
CS
Sauer
Susanne
S
Schuerzinger
Katrin
K
Massberg
Steffen
S
Fitzgerald
Desmond J
DJ
Belton
Orina
O
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D013928:Thromboxane A2 / Q000378:metabolism*; D013929:Thromboxane B2 / Q000378:metabolism
D001057:Apolipoproteins E; D013929:Thromboxane B2; D013928:Thromboxane A2; D051545:Cyclooxygenase 1