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

Little is known about the role of subcellular trafficking of estrogen receptor (ER) subtypes in the acute estrogen (E₂)-mediated alleviation of oxidative stress. We tested the hypothesis that ERα migration to the cardiac myocyte membrane mediates the acute E₂-dependent improvement of cellular redox status.

Myocardial distribution of subcellular ERα, ERβ and G-protein coupled estrogen receptor (GPER) was determined in proestrus sham-operated (SO) and in ovariectomized (OVX) rats, acutely treated with E₂ (1μg/kg) or a selective ERα (PPT), ERβ (DPN) or GPER (G1) agonist (10μg/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.

Compared with SO, OVX rats exhibited higher myocardial ROS and MDA levels, reduced catalase and SOD activities, along with diminished ERα, and enhanced ERβ and GPER, localization at cardiomyocyte membrane. Acute E₂ or an ERα (PPT), but not ERβ (DPN) or GPER (G1), agonist reversed these responses in OVX rats and resulted in higher ERα/ERβ and ERα/GPER ratios at the cardiomyocytes membrane. PPT or DPN enhanced myocardial Akt phosphorylation. We present the first evidence that preferential aggregation of ERα at the cardiomyocytes plasma membrane is ERα-dependent, and underlies E₂-mediated reduction in oxidative stress, at least partly, via the enhancements of myocardial catalase and SOD activities in OVX rats.

The findings highlight ERα agonists as potential therapeutics for restoring the myocardial redox status following E₂ depletion in postmenopausal women.