Differential and opposing regulation of PAI-1 promoter activity by estrogen receptor α and estrogen receptor β in endothelial cells

Layton Harris Smith, Stephen R. Coats, Hao Qin, Matthew S. Petrie, Joseph W. Covington, Ming Su, Mesut Eren, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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 (ERα and ERβ) in regulating the activity of a human PAI-1 promoter reporter construct in transfected bovine aortic endothelial cells (BAECs). ERα increased PAI-1 promoter activity in BAECs by an estrogen-dependent mechanism, whereas ERβ suppressed PAI-1 promoter activity by an estrogen-independent mechanism. The suppressive activity of ERβ was dominant over the inductive activity of ERα. Mutation of a putative estrogen response element (ERE) located at position -427 in the proximal promoter abolished the ERα action without influencing the suppressive effects of ERβ. Mutation of either AP1-like site did not eliminate the ERα or ERβ 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 ERα and ERβ exert differential effects on the PAI-1 promoter activity in transfected BAECs. ERα activated the PAI-1 promoter through a proximal ERE (-427) and possibly additional EREs located within the PAI-1 promoter, whereas ERβ suppressed the promoter construct via an unidentified mechanism. This is the first demonstration of the differential regulation of a vascular gene promoter by ERα and ERβ.

Original languageEnglish (US)
Pages (from-to)269-275
Number of pages7
JournalCirculation research
Volume95
Issue number3
DOIs
StatePublished - Aug 6 2004

Keywords

  • Bovine aortic endothelial cell
  • Estrogen receptors
  • Estrogen response element
  • Plasminogen activator inhibitor-1 promoter

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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