Los Angeles, CA - A new study published this week suggests that pollution and high cholesterol levels may interact to increase the risk of cardiovascular disease [1]. Investigators showed that diesel-exhaust particles and oxidized phospholipids synergistically affect the expression of several genes corresponding to the pathways relevant to the vascular inflammation process, including the development of atherosclerosis.

Using human microvascular endothelial cells (HMEC) as a representative cell type to study the synergistic effects of diesel-exhaust particle chemicals and phospholipid oxidation products on inflammatory gene expression, investigators, led by Dr Ke Wei Gong (University of California Los Angeles), report that both "coregulated a large number of genes that are involved in atherosclerosis and vascular injury associated with ambient particle-matter exposures (PM)."

In the paper, published online July 26, 2007 in Genome Biology, the investigators note that large-scale prospective epidemiological studies have shown that residence in areas with high ambient PM levels is associated with an increased risk of premature cardiopulmonary death, with an approximate 6% increase in cardiopulmonary deaths for every elevation of 10 g/m³ in PM concentration.

Although the mechanism is not fully understood, previous studies examining the effects of diesel exhaust on the lung, for example, have shown that the exhaust is capable of inducing airway inflammation through the generation of reactive oxygen species (ROS) and oxidative stress. With oxidant injury one of the mechanisms of PM-induced pulmonary inflammation, the authors suggest this mechanism might also be applicable to the atherogenic effects of PM, with animal models having also shown that exposure to ambient PM promotes atherosclerosis. Because atherosclerosis is a chronic vascular inflammatory process, where lipid deposition and oxidation in the artery are part of the disease process, investigators wanted to determine whether PM-induced oxidative stress could react synergistically with oxidized lipid components to enhance vascular inflammation, a process that leads to an increase in atherosclerosis.

The UCLA investigators used HMEC to study the combined effects of diesel-exhaust particles and oxidized LDL cholesterol—in this case, oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (ox-PAPC), a biologically active component of modified LDL. The cells were treated in triplicate with an organic diesel-exhaust particle extract, ox-PAPC, or a combination of both compounds for four hours.

The team report that the diesel particles and oxidized phospholipids worked in tandem to activate genes known to be responsible for cellular inflammation. Using a weighted gene coexpression network analysis to identify modules of highly coexpressed genes, they found three modules that were significantly enriched in genes that were regulated by the stimuli. These modules were also enriched in the synergistically coregulated genes and pathways relevant to vascular inflammation.

According to the authors, the interaction left a "genetic footprint" that revealed how the interaction between the pollution and cholesterol accelerates atherosclerosis. The synergy was validated in vivo, report Gong and colleagues, as they also demonstrated that liver gene expression of hypercholesterolemic mice exposed to ambient ultrafine particles exhibited significant upregulation of the module genes.

The authors say the next step will involve converting the genetic response to the pollution-cholesterol interaction into a biomarker that would enable clinicians to evaluate the effect of pollution on a patient's health, with an eye toward identifying those at risk for cardiovascular disease.