Hormone replacement therapy for postmenopausal atherosclerosis is offset by late age iron deposition

Postmenopausal atherosclerosis (AS) has been attributed to estrogen deficiency. However, the beneficial effect of hormone replacement therapy (HRT) is lost in late postmenopausal women with atherogenesis. We asked whether aging-related iron accumulation affects estrogen receptor α (ERα) expression, thus explaining HRT inefficacy. A negative correlation has been observed between aging-related systemic iron deposition and ERα expression in postmenopausal AS patients. In an ovariectomized Apoe(-/-) mouse model, estradiol treatment had contrasting effects on ERα expression in early versus late postmenopausal mice. ERα expression was inhibited by iron treatment in cell culture and iron-overloaded mice. Combined treatment with estradiol and iron further decreased ERα expression, and the latter effect was mediated by iron-regulated E3 ligase Mdm2. In line with these observations, cellular cholesterol efflux was reduced, and endothelial homeostasis was disrupted. Consequently, AS was aggravated. Accordingly, systemic iron chelation attenuated estradiol-triggered progressive AS in late postmenopausal mice. Thus, iron and estradiol together downregulate ERα through Mdm2-mediated proteolysis, providing a potential explanation for failures of HRT in late postmenopausal subjects with aging-related iron accumulation. This study suggests that immediate HRT after menopause, along with appropriate iron chelation, might provide benefits from AS.