Cyclooxygenase-2-Derived Prostacyclin Confers Atheroprotection on Female Mice

Abstract

Before menopause, women are relatively protected against cardiovascular disease. Although estrogen (E2) retards atherogenesis in animal models and improves endothelial function in women with hyperlipidemia, the mechanisms of atheroprotection remain to be defined completely. The prostaglandin PGI2 inhibits platelet activation, vascular smooth muscle contraction, leukocyte-endothelial cell interactions, and cholesteryl ester hydrolase. PGI2 analogs limit atherogenesis, and atherosclerotic lesions have a reduced ability to produce PGI2. Cyclooxygenase 2 (COX-2), expressed in vascular endothelial cells, catalyzes the formation of prostaglandin endoperoxide from arachidonic acid, and this subsequently is transformed to PgI2 in endothelial cells by the action of PGI 2 synthase. Selective COX-2 inhibitors retard the excretion of PGI2 metabolites. These mechanisms may be relevant to atheroprotection in women because E2 increases the expression of COX-2 in vascular tissues and promotes the in vitro production of PGI2. Male mice lacking low-density lipoprotein receptor (LDLR) developed atherosclerosis more rapidly than did females, despite the lack of differences in total plasma cholesterol or high-density lipoprotein cholesterol. Female mice lacking both PGI2 receptor and the LDLR developed more prominent aortic lesions than did LDLR-knockout females (ie, lacking the gene for the LDL receptor). This effect was not gene dose-dependent and was not apparent in male mice. Further observations indicated that PGI2 decreases the platelet activation that characterizes early atherogenesis in female mice. It appears that PGI2 serves as an antioxidant in female LDLR-knockout mice before atherogenesis and at its earliest stage. Adding hydrogen peroxide to cultured mouse aortic smooth muscle cells increased synthesis of PGI2 and lipid peroxidation. There was no change in the expression of COX-2. Peroxide increased reactive oxygen species, and this effect was augmented by the lack of PGI2 receptor expression. These observations suggest that the PGI2 receptor modulates oxidant stress under baseline conditions. Importantly, E2 stimulated COX-2 expression and PGI2 formation. These findings suggest that E2 receptor alpha-mediated COX-2 stimulation of PGI2 makes a substantial contribution to atheroprotection in female LDLR-knockout mice. It is possible that ongoing treatment of patients with selective COX-2 inhibitors might undermine protection from cardiovascular disease in premenopausal females.