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Curcumin regulates prostaglandin (PG) synthesis in a variety of cells. PGE2 and PGI2 are generated from arachidonic acid (AA) by cyclooxygenases 1 and 2 (COX-1 and COX-2) and the synthase (PGES and PGI2S) pathways. This study evaluates the in vitro effect of curcumin on the expression of COX-1, COX-2, PGI2S and microsomal PGES-1 (mPGES-1), and the production of PGE2 and PGI2 in human coronary artery endothelial cells (HCAEC). HCAEC monolayers were incubated with curcumin and the expression of mRNA, protein and the production of PGI2 and PGE2 were quantified. Incubation of HCAEC with curcumin led to a time and concentration-dependent increases in COX-2 mRNA with a small but significant decrease in COX-1 mRNA expression. Curcumin also stimulated the expression of PGI2S and mPGES-1 mRNA. Although curcumin stimulated COX-2, PGI2S and mPGES-1 gene expression, it failed to increase PGI2 or PGE2 production. Interestingly, supplementation of the culture medium with AA increased prostanoid production by both quiescent and curcumin-treated cells. However, in comparison to the quiescent cells, the prostanoid production by curcumin-treated cells was markedly enhanced as AA concentrations in the medium were increased, and the enhanced prostanoid production was blocked by the presence of COX-2 specific inhibitor. Taken together, these results suggest that curcumin regulates prostanoid homeostasis in HCAEC by modulating multiple steps including the expression of COX-1, COX-2, PGI2S and mPGES-1.
The production of thromboxane A2 (TXA2) and prostacyclin (prostaglandin I2, PGI2) is known to be increased in patients with atherosclerosis. In this study, we evaluated the influence of gender on TXA2 and PGI2 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 TXB2 and 2, 3-dinor-6-keto PGF1alpha indicated that female ApoE-/- mice produce up to 15-fold more TXA2 and 50% less PGI2 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 TXA2 production and reduced PGI2 production are gender-related proatherogenic risk factors in female ApoE-/- mice.
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