La Jolla, CA - Chronic exposure to air pollution has previously been linked to cardiovascular disease, and even though the mechanisms were not fully understood, the American Heart Association felt the association was strong enough to warrant issuing a scientific statement on pollution and cardiovascular disease [1].

Now, a new study by Dr Cindy Takeuchi (Scripps Research Institute, La Jolla, CA) and colleagues, published in the June 13, 2006 issue of Biochemistry, appears to have discovered a pathway in which smog, a mixture of pollutants including ozone, is implicated in cardiovascular disease [2]. In vitro experiments have shown that byproducts of cholesterol oxidation, known as atheronals, possess biological effects that may affect atherogenesis and atherosclerotic disease progression.

"These molecules are present in clinical samples, both in plasma and plaque, and are significantly elevated in late-stage cardiovascular disease," senior investigator Dr Paul Wentworth Jr (Scripps Research Institute) told heartwire. "This study shows that the molecules could be contributing to atherosclerosis through a variety of mechanisms."

Atheronals, explained Wentworth, are oxidation products of cholesterol and are present in the body, although how they are generated remains unknown. One theory is that inflammatory cells generate the molecules, with activated white blood cells releasing oxidative species to oxidize cholesterol. The second theory is that atheronal-A and atheronal-B could arise from environmental pollution—that is, from the reaction between ozone and cholesterol in the body.

Wentworth noted that atheronal-A and atheronal-B have been shown to be present within atherosclerotic plaque material at the time of endarterectomy. Atheronal-B has also been shown to be present in human plasma as well as significantly elevated in a small cohort of human patients with atherosclerosis. In the present experiment, investigators sought to determine the biological effects of these cholesterol oxidation products.

In various laboratory experiments, the investigators showed that the atheronals facilitate macrophage recruitment to the vascular tissue through chemotaxis and endothelial adhesion-molecule upregulation. Atheronal-B was also shown to trigger foam-cell formation via scavenger receptor uptake of atheronal-modified LDL cholesterol. The atheronals also caused the differentiation of monocytes into macrophages and were shown to be able to enter macrophages by a receptor-independent process.

"In a nutshell, all the effects of atheronals would serve to trigger atherosclerosis," said Wentworth. "All of these effects are considered to be proatherogenic, and this is how we think they are contributing to disease." He added that while the results suggest a pathway between pollution and heart disease, they also suggest a possible new link between inflammation and cardiovascular disease. Wentworth stressed that these are in vitro experiments and conclusions about in vivo data must be speculative at this stage.

Next steps, Wentworth told heartwire, will be to determine whether the same effects can be replicated in animal models, as they wish to determine how the levels of atheronals in plasma and in plaque correlate with disease progression. In addition, they will be looking to determine causation by examining whether atherosclerosis accelerates on administration of the oxidized cholesterol byproducts. Clinical work will also involve looking at atheronal plasma concentrations of various cohorts to determine whether atheronal levels correlate with disease progression.