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

Smith LH, Petrie MS, Morrow JD, Oates JA, Vaughan DE
J Lipid Res. 2005 46 (5): 862-71

PMID: 15716578 · DOI:10.1194/jlr.M500021-JLR200

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.

MeSH Terms (21)

Animals Base Sequence Cattle CCAAT-Enhancer-Binding Proteins Cells, Cultured Cyclooxygenase 2 DNA-Binding Proteins DNA Primers Endothelium, Vascular Epoprostenol Gene Expression Regulation, Enzymologic Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors Lovastatin Membrane Proteins Promoter Regions, Genetic Prostaglandin-Endoperoxide Synthases Reverse Transcriptase Polymerase Chain Reaction Sterol Regulatory Element Binding Protein 1 Sterol Regulatory Element Binding Protein 2 Transcription Factors

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