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Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1276-82. Epub 2007 Apr 5.

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

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  • 1Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, P.O. Box 801394, Charlottesville, VA, USA.

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.

PMID:
17413033
[PubMed - indexed for MEDLINE]
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