Diesel Fumes Team Up With Cholesterol for Atherosclerosis

LOS ANGELES, July 27 -- Diesel pollution may induce cardiovascular risk, researchers found in a genome-wide study.
Diesel fumes synergistically link up with cholesterol to activate genes that turn up atherosclerosis and vessel inflammation, according to Andre Nel, M.B.Ch.B., Ph.D., of the University of California, Los Angeles, and colleagues.
In vitro and mouse studies revealed that a low dose of diesel exhaust particles combined with oxidized phospholipids generated in LDL cholesterol upregulated 1,555 genes, of which the most upregulated clusters were in pathways related to vascular inflammation and atherosclerosis, they reported in the July 26 issue of Genome Biology.
Of the upregulated genes, 43% exhibited synergy when the diesel particles and oxidized phospholipids were combined.
"Our gene-expression data are of considerable importance in understanding how ambient air pollution might contribute to endothelial injury and to atherosclerosis," they wrote.
Air pollution, particularly ambient particulate matter, has been associated with increased cardiovascular morbidity and mortality in previous studies, although the mechanism has been debated.
But, "it is becoming increasingly clear that particulate matter exerts pro-oxidative and pro-inflammatory effects in the lung that can also spill over to the systemic circulation," they added.
The researchers conducted a series of experiments to clarify how the process occurred. They first looked at heme oxygenase-1, an important oxidative stress sensor in endothelial cells.
They found that human microvascular endothelial cells had a 15-fold higher density of this protein when treated with diesel exhaust particles plus phospholipid oxidation products than when treated with diesel exhaust particles alone and five-fold more than when treated with phospholipid oxidation products alone.
Then, they assessed gene-expression profiles using microarrays and found that at total of 1,555 genes were significantly upregulated by at least 1.5-fold (P<0.05) when the cells were treated with diesel exhaust particles or oxidated phospholipids. Again, the combination showed the largest effect and altered expression of more genes than either alone.
When the genes were grouped using weighted gene coexpression network analysis, 664 of the 1,555 significantly upregulated genes showed synergism when treated with the combination of diesel exhaust and oxidated phospholipids.
Furthermore, 83% of these synergistically expressed genes were concentrated in three groups of densely interconnected genes.
These groups included around 40% of the electrophile-response element-regulated genes, around 58% of the pro-inflammatory response genes, around 84% of the apoptosis pathway genes, and around 79% of the unfolded protein response genes present in entire network.
The synergistic upregulation was confirmed by quantitative polymerase chain reaction (qPCR).
Finally, the researchers showed that these pathways were activated in vivo.
They compared mice fed a high fat diet and exposed to dirty ambient air in a mobile animal laboratory in downtown Los Angeles (concentrated ultrafine particles < 0.18 μm, predominantly diesel exhaust particles) to those exposed to concentrated larger particulate matter (fine particles < 2.5 μm) or to filtered-air or left unexposed.
The mice exposed to the ultrafine, mostly diesel particles, had significantly upregulated genes for heme oxygenase-1, the oxidative stress sensor in endothelial cells, as well as for two key unfolded protein response gene transcription factors compared to the other three groups of mice (P<0.05).
"The systemic effects could result either from the systemic release of inflammatory mediators from the lung or from the possible direct access of particles or chemicals to the systemic circulation," the researchers suggested.
Either way, the interaction of particulate matter vascular endothelium in the lung or systemic circulation "may be relevant in the generation of systemic vascular effects" and, they proposed, may be "magnified by their interaction with oxidized phospholipids generated in LDLs or in the membranes of vascular endothelial cells."
The study was supported by grants from the National Institute of Environmental Health Sciences, the National Institute of Allergy, Immunology and Infectious Diseases, the Robert Wood Johnson Foundation, and the National Heart, Blood and Lung Institute as well as by an award to the Southern California Particle Center. Primary source: Genome BiologySource reference: Gong KW, et al "Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells" Genome Biol 2007.