Published online before print June 24, 2004, doi: 10.1161/01.RES.0000136521.70093.f1
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Differential and Opposing Regulation of PAI-1 Promoter Activity by Estrogen Receptor 
and Estrogen Receptor ß in Endothelial Cells
From the Departments of Medicine and Pharmacology, Vanderbilt University Medical Center and Nashville Veterans Affairs Medical Center, Nashville, Tenn.
Correspondence to Douglas E. Vaughan, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 383 PRB, 2220 Pierce Ave South, Nashville, TN 37232-6300. E-mail doug.vaughan{at}mcmail.vanderbilt.edu
To investigate the molecular mechanisms involved in the estrogen-dependent control of plasminogen activator inhibitor-1 (PAI-1) gene expression in vascular cells, we compared the transactivation properties of estrogen receptors (ER
and ERß) in regulating the activity of a human PAI-1 promoter reporter construct in transfected bovine aortic endothelial cells (BAECs). ER increased PAI-1 promoter activity in BAECs by an estrogen-dependent mechanism, whereas ERß suppressed PAI-1 promoter activity by an estrogen-independent mechanism. The suppressive activity of ERß was dominant over the inductive activity of ER. Mutation of a putative estrogen response element (ERE) located at position –427 in the proximal promoter abolished the ER action without influencing the suppressive effects of ERß. Mutation of either AP1-like site did not eliminate the ER or ERß actions at the PAI-1 promoter, suggesting that other promoter elements are involved in these responses. These mutations significantly reduced the –3.4kbp PAI-1 promoter response to serum. We concluded that ER and ERß exert differential effects on the PAI-1 promoter activity in transfected BAECs. ER activated the PAI-1 promoter through a proximal ERE (–427) and possibly additional EREs located within the PAI-1 promoter, whereas ERß suppressed the promoter construct via an unidentified mechanism. This is the first demonstration of the differential regulation of a vascular gene promoter by ER and ERß.
Key Words: estrogen receptors • plasminogen activator inhibitor-1 promoter • estrogen response element • bovine aortic endothelial cell
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