Estrogen receptor-α but not -β or GPER inhibits high glucose-induced human VSMC proliferation: potential role of ROS and ERK.
BACKGROUND
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 (E(2)) in vascular smooth muscle cells (VSMCs).


OBJECTIVE
Because E(2) 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.


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 E(2), 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 (H(2)O(2)) 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.


CONCLUSIONS
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 E(2) are abolished under HG. Pharmacological activation of ERα may thus have therapeutic potential for treating cardiovascular dysregulation associated with diabetes.
Division of Clinical and Interventional Angiology, University Hospital Bern, Bern, Switzerland. jana.ortmann@insel.ch
Jana
J
Ortmann
Martha
M
Veit
Sandra
S
Zingg
Stefano
S
Di Santo
Tobias
T
Traupe
Zijiang
Z
Yang
Jan
J
Völzmann
Raghvendra K
RK
Dubey
Stephan
S
Christen
Iris
I
Baumgartner
D000704:Analysis of Variance; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013482:Superoxide Dismutase / Q000378:metabolism; D011422:Propionates
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol