Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors.
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.


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.


CONCLUSIONS
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.
Krönke
Gerhard
G
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, P.O. Box 801394, Charlottesville, VA, USA.
Kadl
Alexandra
A
Ikonomu
Elena
E
Blüml
Stefan
S
Fürnkranz
Alexander
A
Sarembock
Ian J
IJ
Bochkov
Valery N
VN
Exner
Markus
M
Binder
Bernd R
BR
Leitinger
Norbert
N
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D008665:Metalloporphyrins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011524:Protoporphyrins / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002839:Chromans; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D008665:Metalloporphyrins; D047493:PPAR alpha; D047495:PPAR gamma; D011524:Protoporphyrins; D011743:Pyrimidines; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; C017803:zinc protoporphyrin; C006253:pirinixic acid; C032628:tin protoporphyrin IX; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000077288:Troglitazone; D011345:Fenofibrate