Air pollutant chemicals and oxidized lipids exhibit genome wide synergistic effects on endothelial cells
Ke Wei Gong , Wei Zhao , Ning Li , Berenice Barajas , Michael Kleinman , Constantinos Sioutas , Steve Horvath , Aldons J Lusis , Andre E Nel and Jesus A Araujo
Genome Biology 2007, 8:R149 doi:10.1186/gb-2007-8-7-r149
Published 26 July 2007
Ambient air pollution is associated with increased cardiovascular morbidity and mortality. We have found that exposure to ambient ultrafine particulate matter (PM), 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 (LDL) particles to enhance vascular inflammation and atherosclerosis.
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 HMEC in triplicate wells with an organic DEP extract (5 micrograms/ml), ox-PAPC (10, 20 and 40 micrograms/ml) or combination of both compounds for 4 hours. Gene expression profiles were assessed by Illumina microarray technology. Both the DEP extract and ox-PAPC co-regulated a large number of genes. We used network analysis to identify co-expressed 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 coregulated genes and pathways relevant to vascular inflammation. We validated this synergy in vivo by demonstrating that liver gene expression of hypercholesterolemic mice exposed to ambient ultrafine particles exhibited significant upregulation of the module genes.
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.