7The sterol response element binding protein regulates cyclooxygenase-2 gene expression in endothelial cells

Layton Harris Smith, Matthew S. Petrie, Jason D. Morrow, John A. Oates, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

We previously demonstrated that cholesterol deprivation increases endothelial cyclooxygenase-2 (COX-2)-dependent prostacyclin [prostaglandin I2 (PGI2)] production in vitro. Cholesterol directly regulates gene transcription through the sterol response element binding protein (SREBP). In this work, we demonstrate that SREBP directly regulates COX-2 expression. Cholesterol reduces human COX-2 promoter-luciferase reporter construct activity in transiently transfected endothelial cells. Conversely, cotransfection with a constitutively active mutant SREBP increases COX-2 promoter activity. SREBP-1a and -2 specifically bind a putative sterol response element (SRE) sequence in the COX-2 promoter. This sequence competes for SREBP binding to a low density lipoprotein receptor consensus sequence in an electromobility-shift assay. These data indicate that endothelial COX-2 is regulated by cholesterol via the SREBP pathway. The present study identifies COX-2 as the first vascular gene without a clear role in lipid metabolism transactivated by SREBP, and suggests that enhanced production of PGI2 through this pathway may be an additional benefit of cholesterol-lowering therapies.

Original languageEnglish (US)
Pages (from-to)862-871
Number of pages10
JournalJournal of lipid research
Volume46
Issue number5
DOIs
StatePublished - 2005

Keywords

  • Cholesterol
  • HMG-CoA reductase inhibitor
  • Lovastatin
  • Prostacyclin
  • Vascular endothelial function

ASJC Scopus subject areas

  • Endocrinology
  • Biochemistry
  • Cell Biology

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