Abstract 3762: Selective Activation of Estrogen Receptor Beta Attenuates Atherogenesis and Represses Cholesterol-associated Immune-inflammatory Responses
Cholesterol-associated immune / inflammatory responses play a critical role in atherogenesis. While estrogen receptor modulation for the prevention of atherosclerosis is currently undergoing reappraisal, it should be noted that estrogen receptor beta (ERβ) has important immune regulatory functions. However, the impact of ERβ activation on atherogenesis and its underlying immune-inflammatory effects is unknown. To determine if selective ERβ activation attenuates atherogenesis and regulates immune-inflammatory responses associated with hypercholesterolemia. Ovariectomized apoE-null mice were fed a high cholesterol diet and received daily s.c. injection for 5 wks with 8β-VE2, a highly selective and potent ERβ agonist (Bayer Schering Pharma). In a separate experiment, primary murine macrophages were treated with oxidized low density lipoproteins (oxLDL) and/or 8β-VE2. Systemic administration of 8β-VE2 resulted in 40% and 75% reductions in aortic arch atherosclerotic lesion size and density, respectively. In addition, 8β-VE2 treatment led to an increase of cellular density in atheroma, while lesions in vehicle-treated mice were more lipid-laden. The observed attenuation of atherosclerosis by 8β-VE2 was ERβ-specific because (i) ICI182780, an ER antagonist completely abrogated the 8β-VE2-dependent atheroprotection and (ii) the uterine wet weight, a sensitive marker of in vivo ERα activation, was unchanged compared to vehicle-treated mice. As total plasma cholesterol levels were comparable between vehicle and 8β-VE2 treatment groups, we asked if the selective activation of ERβ by 8β-VE2 suppresses cholesterol-associated immune-inflammatory responses. Indeed, a high cholesterol diet led to a 12-fold increase of serum IL1β level compared to baseline levels at one week in vehicle-treated mice, and this IL1β increase was reduced by 62% in 8β-VE2-treated animals. Furthermore, in primary murine macrophage cultures, 8β-VE2 inhibited oxLDL-induced production of IL1β and TNFα, as measured in the supernatant by ELISA. Selective activation of ERβ significantly attenuated atherogenesis with a specific reduction of cholesterol-associated immune-inflammatory effects.