on September 4, 2003
Published online before print September 4, 2003, doi: 10.1161/01.ATV.0000094411.98127.5F
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Submitted on August 4, 2003
Accepted on August 26, 2003
Pioglitazone Inhibits LOX-1 Expression in Human Coronary Artery Endothelial Cells by Reducing Intracellular Superoxide Radical Generation
Jawahar L. Mehta *;
From the Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock.
* To whom correspondence should be addressed. E-mail: mehtajl{at}uams.edu.
Objective--LOX-1, a novel lectin-like receptor for oxidized LDL (ox-LDL), is expressed in response to ox-LDL, angiotensin II (Ang II), tumor necrosis factor (TNF)-
, and other stress stimuli. It is highly expressed in atherosclerotic tissues. Peroxisome proliferator-activated receptor (PPAR)-
ligands, such as pioglitazone, exert antiatherosclerotic effects. This study examined the regulation of LOX-1 expression in human coronary artery endothelial cells (HCAECs) by pioglitazone.
Methods and Results--Fourth generation HCAECs were treated with ox-LDL, Ang II, or TNF- with or without pioglitazone pretreatment. All 3 stimuli upregulated LOX-1 expression (mRNA and protein). Pioglitazone, in a concentration-dependent manner, reduced LOX-1 expression (P<0.01 versus ox-LDL, Ang II, or TNF- alone). Ox-LDL, Ang II, and TNF- each enhanced intracellular superoxide radical generation, and pioglitazone pretreatment reduced superoxide generation (P<0.01 versus ox-LDL, Ang II, or TNF-). Furthermore, all 3 stimuli upregulated the expression of the transcription factors nuclear factor-
B and activator protein-1 (determined by electrophoretic mobility shift assay), and pioglitazone pretreatment reduced this expression (P<0.01 versus ox-LDL, Ang II, or TNF-). To determine the biological significance of pioglitazone-mediated downregulation of LOX-1, we studied monocyte adhesion to ox-LDL-treated HCAECs. Pioglitazone reduced the adhesion of monocytes to activated HCAECs in a fashion similar to that produced by antisense to LOX-1 mRNA.
Conclusions--These observations suggest that the PPAR- ligand pioglitazone reduces intracellular superoxide radical generation and subsequently reduces the expression of transcription factors, expression of the LOX-1 gene, and monocyte adhesion to activated endothelium. The salutary effect of PPAR- ligands in atherogenesis may involve the inhibition of LOX-1 and the adhesion of monocytes to endothelium.
Key words: angiotensin • atherosclerosis • endothelium • oxidized LDL • peroxisome proliferator-activated receptor-
•
ligands •
tumor necrosis factor-
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