on April 5, 2007
Published online before print April 5, 2007, doi: 10.1161/ATVBAHA.107.142638
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Submitted on August 15, 2006
Accepted on March 15, 2007
Expression of Heme Oxygenase-1 in Human Vascular Cells Is Regulated by Peroxisome Proliferator-Activated Receptors
Gerhard Krönke ;
From Robert M. Berne Cardiovascular Research Center (G.K., A.K., I.J.S., N.L.) and Department of Pharmacology (N.L.), University of Virginia, Charlottesville, Va; Department of Vascular Biology and Thrombosis Research (G.K., E.I., A.F., V.N.B., B.R.B.), Institute of Immunology (S.B.), and Department of Medical and Chemical Laboratory Diagnostics (M.E.), Medical University of Vienna, Austria.
* To whom correspondence should be addressed. E-mail: nl2q{at}virginia.edu.
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 PPAR
and PPAR
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 PPAR and PPAR, 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.
Key words: atherosclerosis • heme oxygenase • inflammation • PPAR
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