Endogenous biosynthesis of thromboxane and prostacyclin in 2 distinct murine models of atherosclerosis.
Thromboxane A(2) is a potent vasoconstrictor and platelet agonist; prostacyclin is a potent platelet inhibitor and vasodilator. Altered biosynthesis of these eicosanoids is a feature of human hypercholesterolemia and atherosclerosis. This study examined whether in 2 murine models of atherosclerosis their levels are increased and correlated with the evolution of the disease. Urinary 2,3-dinor thromboxane B(2) and 2,3-dinor-6-keto prostaglandin F(1 alpha), metabolites of thromboxane and prostacyclin, respectively, were assayed in apoliprotein E (apoE)-deficient mice on chow and low-density lipoprotein receptor (LDLR)-deficient mice on chow and a Western-type diet. Atherosclerosis lesion area was measured by en face method. Both eicosanoids increased in apoE-deficient mice on chow and in LDLR-deficient mice on a high-fat diet, but not in LDLR-deficient mice on chow by the end of the study. Aspirin suppressed ex vivo platelet aggregation, serum thromboxane B(2), and 2,3-dinor thromboxane B(2), and significantly reduced the excretion of 2,3-dinor-6-keto prostaglandin F(1 alpha) in these animals. This study demonstrates that thromboxane as well as prostacyclin biosynthesis is increased in 2 murine models of atherogenesis and is secondary to increased in vivo platelet activation. Assessment of their generation in these models may afford the basis for future studies on the functional role of these eicosanoids in the evolution and progression of atherosclerosis. (Blood. 2000;96:3823-3826)
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Center for Experimental Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. domenico@spirit.gcrc.upenn.edu
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D000367:Age Factors; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000293:injuries; D001161:Arteriosclerosis / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000096:biosynthesis; D011464:Epoprostenol / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D015186:Hominidae / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000097:blood; D011460:Prostaglandins F / Q000652:urine; D011973:Receptors, LDL / Q000235:genetics; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000097:blood; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000652:urine
D015777:Eicosanoids; D010975:Platelet Aggregation Inhibitors; D011460:Prostaglandins F; D011973:Receptors, LDL; D013929:Thromboxane B2; D013928:Thromboxane A2; C028965:2,3-dinor-thromboxane B2; D011464:Epoprostenol; D001241:Aspirin; C100006:prostaglandin F1