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

Author:

Xu Tianze1,Cai Jing1,Wang Lei1,Xu Li2,Zhao Hongting2,Wang Fudi3,Meyron-Holtz Esther4,Missirlis Fanis5ORCID,Qiao Tong1,Li Kuanyu12ORCID

Affiliation:

1. State Key Laboratory of Pharmaceutical Biotechnology, Department of Vascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School

2. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University

3. Department of Nutrition, School of Public Health, School of Medicine, Zhejiang University

4. Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology

5. Department of Physiology, Biophysics and Neuroscience

Abstract

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 α (ERα) expression explaining HRT inefficacy. A negative correlation between aging-related systemic iron deposition and ERα expression in postmenopausal AS patients was established. 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, 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 ERα 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.

Publisher

eLife Sciences Publications, Ltd

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3