Submitted on January 18, 2005
Revised on February 8, 2005
Accepted on February 8, 2005
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
Department of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
Corresponding Author: doug.vaughan{at}vanderbilt.edu
We previously demonstrated that cholesterol deprivation increases endothelial cyclooxygenase-2 (COX-2) dependent prostacyclin (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, co-transfection 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 an LDL-R 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 non-cholesterolgenic gene target transactivated by SREBP, and suggests that enhanced production of PGI2 through this pathway may be an additional benefit of cholesterol-lowering therapies.
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