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Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells

Ke Wei Gong1, Wei Zhao2, Ning Li1, Berenice Barajas1, Michael Kleinman3, Constantinos Sioutas4, Steve Horvath2, Aldons J Lusis1, Andre Nel1* and Jesus A Araujo1

Author Affiliations

1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA

2 Departments of Human Genetics and Biostatistics, University of California, Los Angeles, CA 90095, USA

3 Department of Community and Environmental Medicine, University of California, Irvine, CA 92697, USA

4 Department of Civil and Environmental Engineering, University of Southern California, Los Angeles, CA 90089, USA

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Genome Biology 2007, 8:R149  doi:10.1186/gb-2007-8-7-r149

Published: 26 July 2007

Abstract

Background

Ambient air pollution is associated with increased cardiovascular morbidity and mortality. We have found that exposure to ambient ultrafine particulate matter, highly enriched in redox cycling organic chemicals, promotes atherosclerosis in mice. We hypothesize that these pro-oxidative chemicals could synergize with oxidized lipid components generated in low-density lipoprotein particles to enhance vascular inflammation and atherosclerosis.

Results

We have used human microvascular endothelial cells (HMEC) to study the combined effects of a model air pollutant, diesel exhaust particles (DEP), and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (ox-PAPC) on genome-wide gene expression. We treated the cells in triplicate wells with an organic DEP extract, ox-PAPC at various concentrations, or combinations of both for 4 hours. Gene-expression profiling showed that both the DEP extract and ox-PAPC co-regulated a large number of genes. Using network analysis to identify coexpressed gene modules, we found three modules that were most highly enriched in genes that were differentially regulated by the stimuli. These modules were also enriched in synergistically co-regulated genes and pathways relevant to vascular inflammation. We validated this synergy in vivo by demonstrating that hypercholesterolemic mice exposed to ambient ultrafine particles exhibited significant upregulation of the module genes in the liver.

Conclusion

Diesel exhaust particles and oxidized phospholipids synergistically affect the expression profile of several gene modules that correspond to pathways relevant to vascular inflammatory processes such as atherosclerosis.