Abstract
Objective:
Activation of peroxisome proliferator-activated receptors (PPARs) by lipid-lowering fibrates and insulin-sensitizing thiazolidinediones inhibits vascular inflammation, atherosclerosis, and restenosis. Here we investigate if the vasculoprotective and anti-inflammatory enzyme heme oxygenase-1 (HO-1) is regulated by PPAR ligands in vascular cells.
Methods and results:
We show that treatment of human vascular endothelial and smooth muscle cells with PPAR ligands leads to expression of HO-1. Analysis of the human HO-1 promoter in transient transfection experiments together with mutational analysis and gel shift assays revealed a direct transcriptional regulation of HO-1 by PPARalpha and PPARgamma via 2 PPAR responsive elements. We demonstrate that a clinically relevant polymorphism within the HO-1 promoter critically influences its transcriptional activation by both PPAR isoforms. Moreover, inhibition of HO-1 enzymatic activity reversed PPAR ligand-mediated inhibition of cell proliferation and expression of cyclooxygenase-2 in vascular smooth muscle cells.
Conclusion:
We demonstrate that HO-1 expression is transcriptionally regulated by PPARalpha and PPARgamma, indicating a mechanism of anti-inflammatory and antiproliferative action of PPAR ligands via upregulation of HO-1. Identification of HO-1 as a target gene for PPARs provides new strategies for therapy of cardiovascular diseases and a rationale for the use of PPAR ligands in the treatment of other chronic inflammatory diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents / pharmacology
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Cell Proliferation
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Cells, Cultured
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Chromans / pharmacology
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Cyclooxygenase 2 / biosynthesis
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology*
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Fenofibrate / pharmacology
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Heme Oxygenase-1 / antagonists & inhibitors
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Heme Oxygenase-1 / biosynthesis*
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Heme Oxygenase-1 / genetics
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Humans
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Membrane Proteins / biosynthesis
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Metalloporphyrins / pharmacology
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / enzymology*
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Mutation
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / enzymology*
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PPAR alpha / agonists
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PPAR alpha / genetics
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PPAR alpha / metabolism*
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PPAR gamma / agonists
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PPAR gamma / genetics
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PPAR gamma / metabolism*
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Polymorphism, Genetic
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Promoter Regions, Genetic
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Protoporphyrins / pharmacology
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Pyrimidines / pharmacology
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RNA, Messenger / biosynthesis
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Rosiglitazone
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Thiazolidinediones / pharmacology
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Time Factors
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Transcription, Genetic* / drug effects
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Transfection
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Troglitazone
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Inflammatory Agents
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Chromans
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Enzyme Inhibitors
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Membrane Proteins
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Metalloporphyrins
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PPAR alpha
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PPAR gamma
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Protoporphyrins
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Pyrimidines
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RNA, Messenger
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Thiazolidinediones
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Tumor Necrosis Factor-alpha
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Rosiglitazone
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zinc protoporphyrin
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pirinixic acid
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tin protoporphyrin IX
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HMOX1 protein, human
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Heme Oxygenase-1
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Cyclooxygenase 2
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PTGS2 protein, human
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Troglitazone
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Fenofibrate