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Increased aortic atherosclerotic plaque development in female apolipoprotein E-null mice is associated with elevated thromboxane A2 and decreased prostacyclin production.

The production of thromboxane A(2) (TXA(2)) and prostacyclin (prostaglandin I(2), PGI(2)) is known to be increased in patients with atherosclerosis. In this study, we evaluated the influence of gender on TXA(2) and PGI(2) production, and their association with the progression of atherosclerosis in apolipoprotein E-null (ApoE(-/-)) mice maintained on a high fat diet for 3 months. En face analyses of aortas showed marked increases in plaque formation in female ApoE(-/-) mice. Quantification of the hematoxylin/eosin (H&E) stained cross sections of the aortic arch revealed 3 to 4-fold higher plaque thickness in female ApoE(-/-) mice. Analyses of 24-hours urine samples for 11-dehydro TXB(2) and 2, 3-dinor-6-keto PGF(1a) indicated that female ApoE(-/-) mice produce up to 15-fold more TXA(2) and 50% less PGI(2) than the age matched males. Interestingly, the serum cholesterol levels in ApoE(-/-) females were 20% lower than males on the high fat regimen. No gender-associated changes in the number of T lymphocytes, mast cells and macrophages were evident in the lesion areas of ApoE(-/-) mice. The results suggest that the markedly elevated TXA(2) production and reduced PGI(2) production are gender-related proatherogenic risk factors in female ApoE(-/-) mice.