Estrogen Receptor-α But Not -β or GPER Inhibits High Glucose-Induced Human VSMC Proliferation: Potential Role of ROS and ERK

• Published in: The journal of clinical endocrinology and metabolism 2011-01, Vol.96 (1), p.220-228
• Main Authors: Ortmann, Jana, Veit, Martha, Zingg, Sandra, Di Santo, Stefano, Traupe, Tobias, Yang, Zijiang, Völzmann, Jan, Dubey, Raghvendra K, Christen, Stephan, Baumgartner, Iris
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Aorta - cytology; Aorta - drug effects; Aorta - metabolism; Biological and medical sciences; Blotting, Western; Cell Proliferation - drug effects; Cells, Cultured; Endocrinopathies; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Humans; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Nitriles - pharmacology; Original; Phenols - pharmacology; Phosphorylation - drug effects; Pyrazoles - pharmacology; Reactive Oxygen Species - metabolism; Statistics, Nonparametric; Superoxide Dismutase - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2010-0943

Context: The decreased incidence of cardiovascular disease in premenopausal women has been attributed, at least partially, to protective effects of estrogens. However, premenopausal women with diabetes mellitus are no longer selectively protected. High-glucose (HG) conditions have previously been shown to abolish the antimitogenic effects of 17β-estradiol (E2) in vascular smooth muscle cells (VSMCs). Objective: Because E2 mediates its action via different estrogen receptor (ER) subtypes, we hypothesized that different subtypes may have different, if not opposing, effects on HG-induced VSMC proliferation. Methods and Results: Treatment of human aortic VSMCs isolated from premenopausal women with the selective ERα agonist, 4,4′,4′-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol, but not with E2, the selective ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, or the selective G protein-coupled ER agonist G-1 completely prevented increased HG-induced VSMC proliferation. Under these conditions, ERα activation selectively prevented increased hydrogen peroxide (H2O2) and total intracellular reactive oxygen species (ROS) production, caused up-regulation of manganese superoxide dismutase protein and activity, and inhibited prolonged ERK phosphorylation. The latter was mediated by ROS, and ROS inhibition reversed HG-induced ERK-dependent VSMC proliferation. The selective coactivation of ERβ reversed the antimitogenic and antioxidative effects of ERα as well as the up-regulation of manganese superoxide dismutase protein expression. Conclusion: Selective activation of ERα is required for reducing oxidative stress and the consequent hyperproliferation of VSMCs under HG. Our results may further suggest that ERα activation inhibits HG-induced proliferation by down-regulating ROS-mediated ERK activation and may explain why antimitogenic effects of E2 are abolished under HG. Pharmacological activation of ERα may thus have therapeutic potential for treating cardiovascular dysregulation associated with diabetes. Selective activation of estrogen receptor α is required to inhibit vascular smooth muscle cell proliferation induced by high glucose, possibly caused by reactive oxygen species-dependent activation of ERK.