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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence
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CCAAT-Enhancer-Binding Proteins / physiology*
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Cattle
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Cells, Cultured
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Cyclooxygenase 2
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DNA Primers
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DNA-Binding Proteins / physiology*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology*
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Endothelium, Vascular / metabolism
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Epoprostenol / biosynthesis
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Gene Expression Regulation, Enzymologic / physiology*
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Lovastatin / pharmacology
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Membrane Proteins
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Promoter Regions, Genetic
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Prostaglandin-Endoperoxide Synthases / genetics*
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Reverse Transcriptase Polymerase Chain Reaction
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Transcription Factors / physiology*
Substances
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CCAAT-Enhancer-Binding Proteins
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DNA Primers
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DNA-Binding Proteins
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Membrane Proteins
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SREBF1 protein, human
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SREBF2 protein, human
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Transcription Factors
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Lovastatin
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Epoprostenol
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases