Aging-related iron deposit prevents the benefits of HRT from late postmenopausal atherosclerosis

Postmenopausal atherosclerosis has been attributed to estrogen deficiency. The beneficial effect of hormone replacement therapy (HRT), however, is lost in late postmenopausal women with atherogenesis. We asked whether aging-related iron accumulation affects estrogen receptor (ER) expression explaining HRT inefficacy. A negative correlation between aging-related systemic iron deposition and ER expression in postmenopausal AS patients was established. In an ovariectomized ApoE-/- mouse model, estradiol treatment had contrasting effects on ER expression in early versus late postmenopausal mice. ER expression was inhibited by iron treatment in cell culture and iron-overloaded mice. Combined treatment with estradiol and iron further decreased ER expression, mediated by iron-regulated E3 ligase Mdm2. In line with these observations, cellular cholesterol efflux was reduced and endothelial homeostasis was disrupted and, consequently, atherosclerosis was aggravated. Accordingly, systemic iron chelation attenuated estradiol-triggered progressive atherosclerosis in late postmenopausal mice. Thus, iron and estradiol together downregulate ER through Mdm2-mediated proteolysis, explaining failures of HRT in late postmenopausal subjects with aging-related iron accumulation. HRT is recommended immediately after menopause along with appropriate iron chelation to protect from atherosclerosis.