Contribution of cyclooxygenase-1 to thromboxane formation, platelet-vessel wall interactions and atherosclerosis in the ApoE null mouse.

Abstract

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.

METHODS AND 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).

CONCLUSION:

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.

• Authors: Sarah McClelland, Meinrad Gawaz, Elisabeth Kennerknecht, Carolin Sophie Ildiko Konrad, Susanne Sauer, Katrin Schuerzinger, Steffen Massberg, Desmond J Fitzgerald, Orina Belton
• Journal: Atherosclerosis (Atherosclerosis) Vol. 202 Issue 1 Pg. 84-91 (Jan 2009) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 18514659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Thromboxane B2
• Thromboxane A2
• Cyclooxygenase 1

Topics

• Animals
• Aorta, Thoracic (metabolism)
• Apolipoproteins E (genetics)
• Atherosclerosis (metabolism)
• Blood Platelets (metabolism)
• Cyclooxygenase 1 (physiology)
• Endothelium, Vascular (metabolism)
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Biological
• Thromboxane A2 (metabolism)
• Thromboxane B2 (metabolism)