Structure-function relationship of estrogen receptors in cardiovascular pathophysiological models

被引:10
作者
Arnal, Jean-Francois [1 ]
Valera, Marie-Cecile
Payrastre, Bernard
Lenfant, Francoise
Gourdy, Pierre
机构
[1] Univ Toulouse, Fac Med, INSERM, U1048,I2MC, F-31432 Toulouse, France
关键词
VASCULAR INJURY RESPONSE; HORMONE-THERAPY; POSTMENOPAUSAL WOMEN; ACTIVATION-FUNCTION; PROMOTER-CONTEXT; ER-ALPHA; BETA; ESTRADIOL; DISEASE; RISK;
D O I
10.1016/j.thromres.2012.08.261
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The ancestral status of estrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of estrogens, and in particular of 17 beta-estradiol (E2). Indeed, in addition to their well described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes several highly beneficial effects such as prevention of osteoporosis, atheroma and type 2 diabetes,. However, estrogens also promotes two deleterious actions : the stimulation of the proliferation of the epithelium of two sex targets : uterus and breast, favoring an increase in risk of epithelial cancer in these two tissues. These actions are mediated by the activation of ER alpha (ERa) and beta (ER beta), which regulate target gene transcription (genomic action) through two independent activation functions AF-1 and AF-2, but can also elicit rapid membrane initiated steroid signals. Although ER beta plays an important role in the central nervous system and in the heart, ERa appears to play a prominent role in most of the other tissues. One major challenge consists in uncoupling some beneficial actions from other deleterious ones, i. e. selective ER modulation. Tamoxifen and raloxifen are beneficial to prevent the recurrence of breast cancer, and mimic estrogen action mainly on bone, but their effets on atheroma and on type 2 diabetes are if any marginal. These last years, several labs, and in particular our lab, have attempted: 1) To perform an in vivo molecular "dissection" of ERa, allowing the uncoupling of some of its actions, and potentially paving the way to optimized selective ER modulators. (reviewed in Arnal JF, et al. Br J Pharmacol. 2012; 165: 57-66). 2) To describe an unexpected action of E2 treatment at the level of platelet responses in mice, that protects the animals from thromboembolism through the haematopoietic ERa. (Valera MC et al. Blood. 2012, in press). (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:S7 / S11
页数:5
相关论文
共 62 条
[41]   Integration of the extranuclear and nuclear actions of estrogen [J].
Levin, ER .
MOLECULAR ENDOCRINOLOGY, 2005, 19 (08) :1951-1959
[42]   ALTERATION OF REPRODUCTIVE FUNCTION BUT NOT PRENATAL SEXUAL DEVELOPMENT AFTER INSERTIONAL DISRUPTION OF THE MOUSE ESTROGEN-RECEPTOR GENE [J].
LUBAHN, DB ;
MOYER, JS ;
GOLDING, TS ;
COUSE, JF ;
KORACH, KS ;
SMITHIES, O .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (23) :11162-11166
[43]   Combinatorial control of gene expression by nuclear receptors and coregulators [J].
McKenna, NJ ;
O'Malley, BW .
CELL, 2002, 108 (04) :465-474
[44]   Molecular and cellular basis of cardiovascular gender differences [J].
Mendelsohn, ME ;
Karas, RH .
SCIENCE, 2005, 308 (5728) :1583-1587
[45]   Estrogen receptor-α directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter [J].
Métivier, R ;
Penot, G ;
Hübner, MR ;
Reid, G ;
Brand, H ;
Kos, M ;
Gannon, F .
CELL, 2003, 115 (06) :751-763
[46]   Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm [J].
Miyagawa, K ;
Rosch, J ;
Stanczyk, F ;
Hermsmeyer, K .
NATURE MEDICINE, 1997, 3 (03) :324-327
[47]   Estrogen receptor-α mediates the protective effects of estrogen against vascular injury [J].
Pare, G ;
Krust, A ;
Karas, RH ;
Dupont, S ;
Aronovitz, M ;
Chambon, P ;
Mendelsohn, ME .
CIRCULATION RESEARCH, 2002, 90 (10) :1087-1092
[48]   Estrogen Receptor-β Prevents Cardiac Fibrosis [J].
Pedram, Ali ;
Razandi, Mahnaz ;
O'Mahony, Fiona ;
Lubahn, Dennis ;
Levin, Ellis R. .
MOLECULAR ENDOCRINOLOGY, 2010, 24 (11) :2152-2165
[49]   The AF-1 activation-function of ERα may be dispensable to mediate the effect of estradiol on endothelial NO production in mice [J].
Pendaries, C ;
Darblade, B ;
Rochaix, P ;
Krust, A ;
Chambon, P ;
Korach, KS ;
Bayard, F ;
Arnal, JF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (04) :2205-2210
[50]   Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor α [J].
Qing, L ;
Pallas, DC ;
Surks, HK ;
Baur, WE ;
Mendelsohn, ME ;
Karas, RH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (49) :17126-17131