Abstract 18427: 27-Hydroxycholesterol, the First Identified endogenous SERM, Promotes Atherogenesis in Mice
Estrogen has important impact on cardiovascular health, and in mice estrogen actions mediated by estrogen receptor (ER) α prevent atherosclerosis and promote reendothelialization. Previously we discovered that the cholesterol metabolite 27-hydroxycholesterol (27HC), which is elevated with hypercholesterolemia, is an endogenous selective ER modulator (SERM). In mice we found that elevations in 27HC alter vascular ER target gene expression, and they blunt the promotion of carotid artery reendothelialization by estradiol (E2). In the present study, we determined how 27HC impacts atherogenesis. Mice null for the 27HC metabolizing enzyme cyp7b1 (cyp7b1−/−) were crossed with apoE−/− mice to yield apoE+/+;cyp7b1+/+, apoE+/+;cyp7b−/−, apoE−/−;cyp7b1+/+ and apoE−/−;cyp7b1−/− littermates. ApoE+/+;cyp7b1−/− mice on chow diet, who had normal cholesterol and triglyceride levels and serum 27HC levels that were 5.3 and 2.8 fold higher than wild-type in males and females, respectively, developed modest atherosclerosis by 6 months of age. ApoE−/−;cyp7b1−/− mice on chow had elevated cholesterol and triglyceride levels comparable to those of apoE−/−;cyp7b1+/+, but their serum 27HC was increased an additional 36–60%. ApoE−/−;cyp7b1−/− had 35–50% more aortic root lesion area than apoE−/−;cyp7b1+/+ at 6 months of age, and at 12 months lesions were 53–61% larger. Findings were comparable in males and females, and similar differences were noted between genotypes in younger males fed high fat and high cholesterol diet for 8 weeks. In ovariectomized females on high fat and high cholesterol diet for 8 weeks, physiologic doses of E2 provided atheroprotection in apoE−/−;cyp7b1+/+, but not in apoE−/−;cyp7b1−/−. In contrast, pharmacologic doses of E2 provided protection in both groups. 27HC induced the expression of the inflammatory cytokines TNFα, IL-1β, and IL-6 in primary macrophages from wild-type, but not from ERα−/− mice, suggesting that 27HC augments atherogenic inflammation in an ERα-dependent manner. Thus, 27HC promotes atherosclerotic lesion development independent from cholesterol levels, and it exacerbates atherosclerosis invoked by hypercholesterolemia, and these processes are likely mediated by 27HC actions as a SERM.
- © 2010 by American Heart Association, Inc.