Published online before print September 4, 2003, doi: 10.1161/01.ATV.0000094411.98127.5F
© 2003 American Heart Association, Inc.
Vascular Biology |
Pioglitazone Inhibits LOX-1 Expression in Human Coronary Artery Endothelial Cells by Reducing Intracellular Superoxide Radical Generation
From the Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR.
Correspondence to J.L. Mehta, MD, PhD, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, No. 532, Little Rock, AR 72205. 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 • oxidized LDL • peroxisome proliferator–activated receptor- • tumor necrosis factor-
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