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Journal of Lipid Research, Vol. 46, 862-871, May 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

The 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^,** and Douglas E. Vaughan^1,,

^* Departments of Pharmacology, Vanderbilt University Medical Center, Nashville, TN
Medicine, Vanderbilt University Medical Center, Nashville, TN
^** Divisions of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN

¹ To whom correspondence should be addressed. e-mail: doug.vaughan{at}vanderbilt.edu

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.

Abbreviations: COX, cyclooxygenase; FBS, fetal bovine serum; HUVEC, human umbilical vein endothelial cell; LDL, low density lipoprotein; PGE₂, prostaglandin E₂; PGI₂, prostaglandin I₂; SREBP, sterol response element binding protein

Supplementary key words prostacyclin • cholesterol • HMG-CoA reductase inhibitor • lovastatin • vascular endothelial function

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