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Estrogen Receptor- But Not -β or GPER Inhibits High Glucose-Induced Human VSMC Proliferation: Potential Role of ROS and ERK
- Source :
- The Journal of Clinical Endocrinology & Metabolism; January 2011, Vol. 96 Issue: 1 p220-228, 9p
- Publication Year :
- 2011
-
Abstract
- 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 E2mediates 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 ER 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, ER 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 ER as well as the up-regulation of manganese superoxide dismutase protein expression. CONCLUSION: Selective activation of ER is required for reducing oxidative stress and the consequent hyperproliferation of VSMCs under HG. Our results may further suggest that ER activation inhibits HG-induced proliferation by down-regulating ROS-mediated ERK activation and may explain why antimitogenic effects of E2are abolished under HG. Pharmacological activation of ER may thus have therapeutic potential for treating cardiovascular dysregulation associated with diabetes.
Details
- Language :
- English
- ISSN :
- 0021972X and 19457197
- Volume :
- 96
- Issue :
- 1
- Database :
- Supplemental Index
- Journal :
- The Journal of Clinical Endocrinology & Metabolism
- Publication Type :
- Periodical
- Accession number :
- ejs22990152