Rebecca J Steagall1, Fanrong Yao1, Saame Raza Shaikh2, Abdel A Abdel-Rahman3. 1. Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. 2. Department of Biochemistry and Molecular Biology, East Carolina Diabetes & Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. 3. Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address: abdelrahmana@ecu.edu.
Abstract
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: The findings highlight ERα agonists as potential therapeutics for restoring the myocardial redox status following E2 depletion in postmenopausal women.
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: The findings highlight ERα agonists as potential therapeutics for restoring the myocardial redox status following E2 depletion in postmenopausal women.
Authors: S R Stauffer; C J Coletta; R Tedesco; G Nishiguchi; K Carlson; J Sun; B S Katzenellenbogen; J A Katzenellenbogen Journal: J Med Chem Date: 2000-12-28 Impact factor: 7.446
Authors: Hao Wang; Xuming Sun; Marina S Lin; Carlos M Ferrario; Holly Van Remmen; Leanne Groban Journal: Transl Res Date: 2018-04-25 Impact factor: 7.012