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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1276.)
© 2007 American Heart Association, Inc.

Vascular Biology

Expression of Heme Oxygenase-1 in Human Vascular Cells Is Regulated by Peroxisome Proliferator-Activated Receptors

Gerhard Krönke; Alexandra Kadl; Elena Ikonomu; Stefan Blüml; Alexander Fürnkranz; Ian J. Sarembock; Valery N. Bochkov; Markus Exner; Bernd R. Binder; Norbert Leitinger

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.

Correspondence to Norbert Leitinger, PhD, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, P.O. Box 801394 Charlottesville, VA. 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.

We investigated if the vasculoprotective activity of PPARs could be mediated by expression of HO-1. We found that PPAR and PPAR ligands upregulate HO-1 expression in vascular cells via 2 PPAR responsive elements. In addition, PPAR-induced HO-1 mediated anti-inflammatory and antiproliferative action of PPAR-ligands in smooth muscle cells.

Key Words: atherosclerosis • heme oxygenase • inflammation • PPAR

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