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


CONCLUSIONS
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.
Gong
Ke Wei
KW
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Zhao
Wei
W
Li
Ning
N
Barajas
Berenice
B
Kleinman
Michael
M
Sioutas
Constantinos
C
Horvath
Steve
S
Lusis
Aldons J
AJ
Nel
Andre
A
Araujo
Jesus A
JA
D000393:Air Pollutants / Q000633:toxicity*; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D010713:Phosphatidylcholines / Q000633:toxicity*; D014657:Vasculitis / Q000139:chemically induced / Q000235:genetics; D001335:Vehicle Emissions / Q000633:toxicity*
D000393:Air Pollutants; D010713:Phosphatidylcholines; D001335:Vehicle Emissions; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D051547:Heme Oxygenase-1