Estrogen receptor α activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats

Aims: Little is known about the role of subcellular trafficking of estrogen receptor (ER) subtypes in the acute estrogen (E-2)-mediated alleviation of oxidative stress. We tested the hypothesis that ER alpha migration to the cardiac myocyte membrane mediates the acute E-2-dependent improvement of cellular redox status. Main methods: Myocardial distribution of subcellular ER alpha, ER beta and G-protein coupled estrogen receptor (GPER) was determined in proestrus sham-operated (SO) and in ovariectomized (OVX) rats, acutely treated with E-2 (1 mu g/kg) or a selective ER alpha (PPT), ER beta (DPN) or GPER (G1) agonist (10 mu g/kg), by immunofluorescence and Western blot. We measured ROS and malondialdehyde (MDA) levels, and catalase and superoxide dismutase (SOD) activities to evaluate myocardial antioxidant/redox status. Key findings: Compared with SO, OVX rats exhibited higher myocardial ROS and MDA levels, reduced catalase and SOD activities, along with diminished ER alpha, and enhanced ER beta and GPER, localization at cardiomyocyte membrane. Acute E-2 or an ER alpha (PPT), but not ER beta (DPN) or GPER (G1), agonist reversed these responses in OVX rats and resulted in higher ER alpha/ER beta and ER alpha/GPER ratios at the cardiomyocytes membrane. PPT or DPN enhanced myocardial Akt phosphorylation. We present the first evidence that preferential aggregation of ER alpha at the cardiomyocytes plasma membrane is ER alpha-dependent, and underlies E-2-mediated reduction in oxidative stress, at least partly, via the enhancements of myocardial catalase and SOD activities in OVX rats. Significance: The findings highlight ER alpha agonists as potential therapeutics for restoring the myocardial redox status following E-2 depletion in postmenopausal women. (C) 2017 Elsevier Inc. All rights reserved.