Abstract 13763: Reducing Cardiovascular Disease Risk by Estrogen Treatment After Surgical Menopause in Combination With the Suppression of Interferon Gamma Pathway in Ldlr Null Mice

Atherosclerotic cardiovascular disease (ASCVD) risk is increased in women after menopause, which has not been shown to be reversed by postmenopausal hormone therapy. To understand the underlying mechanism for the lack of improvement in ASCVD with hormone therapy, Ldlr ^-/- mice with established atherosclerosis were subjected to procedures of surgical menopause (ovariectomy, ovx), 17β-estradiol (E ₂ ) treatment after ovariectomy (ovx+E ₂ ), or sham. In all groups, hyperlipidemia was normalized with a chow diet. Ten weeks later, atherosclerosis burden and ASCVD risk were evaluated. Atherosclerosis was reversed by the resolution of hyperlipidemia in sham but not ovx nor ovx+E ₂ mice. While E ₂ treatment improved lipid management in ovx mice, we observed persistent inflammation, which presented as high levels of IFNγ, IL-6, and C-PEP2 as well as impaired HDL anti-atherogenic functions and unresolved inflammation in the atherosclerosis lesion. To further investigate the role of inflammation in persistent ASCVD during hormone therapy, the interferon gamma (IFNγ) pathway was suppressed in a second cohort of Ldlr ^-/- mice that were constituted with bone marrow from Ifn γ ^-/- mice following lethal irradiation. Similar to the 1 ^st cohort of mice, E ₂ treatment improved ASCVD risk factors including hyperlipidemia and insulin actions. In mice carrying IFNγ ^-/- bone marrow, atherosclerosis lesion size was reversed with E ₂ treatment, which was associated with decreased IFNγ and IL-6 in the blood. We are further investigating the HDL functions and lesion inflammation in this cohort. Our studies indicate that limiting inflammation may be needed in order to restore the cardiovascular benefits of menopause E ₂ treatment.