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New light on the role of microbial pathogens in atherosclerosis

October 11, 1999

Cardiovascular disease is the leading cause of death in industrialized countries (32% of all deaths in France, for example), and atherosclerosis is often the underlying process. Genetic and environmental factors (such as smoking, obesity, hypertension and high cholesterol levels) are known to play a role in atherosclerosis, but various lines of evidence also suggest that microbial pathogens are involved in the formation of atheroma plaque (i.e. atherosclerosis) or in its rupture (potentially leading to cardiovascular events). Bacteria (especially Chlamydia pneumoniae) and viruses have been detected at an abnormally high frequency in atheroma plaque, and have been forwarded either as co-factors in people already at risk, or as the chief cause of atherosclerosis in people with none of the classical risk factors.

Alain Tedgui, Ziad Mallat (Inserm unit 141, headed by Bernard Lévy) and their coworkers found that microbial pathogens induced atherosclerosis in experimental mice when an antiinflammatory cytokine, interleukin 10 (IL-10), was lacking. IL-10 production is under genetic control. Between 50 and 60% of the human population can produce high levels of this cytokine, while 40 to 50% produce intermediate levels and 5 to 10% can only synthesize small amounts.

The Inserm team worked on a mouse strain deficient in IL-10. The animals were raised in cages with filtered air (protecting them from air-borne microbes), and received a diet designed to induce atheroma plaque. The researchers found that the plaques were three times bigger than in similarly treated mice with normal IL-10 production, thereby demonstrating that IL-10 limits atheroma plaque formation.
The team then examined what happened when IL-10-deficient mice and their normal counterparts mice were exposed to unfiltered air containing microbial pathogens. This time the atheroma plaques in the deficient mice were 30 times larger than in their IL-10-producing counterparts. In other words, exposure to air-borne pathogens multiplied atheroma plaque formation by a factor of 10 in IL-10-deficient mice.

Finally, the researchers examined the composition of the atheroma plaque (proportions of lipids, macrophages, fibers and muscle cells), because this is an important factor in its stability, i.e. its tendency to break free from the vessel wall. The proportion of collagen fibers - a factor protecting against rupture - was four times lower in IL-10-deficient mice than in normal mice. Thus, the absence of IL-10 not only multiplied by a factor of 10 the size of the atheroma plaque when mice were exposed to air-borne pathogens, but it also made the plaque far more likely to rupture.

These results, published by Inserm unit 141, pave the way for studies designed to examine whether the risk of human cardiovascular disease is linked to IL-10 production capacity. They also lay the foundations for studies that may finally show whether certain microbial pathogens are involved in atherosclerosis.

If confirmed in humans, these findings may shortly lead to new treatment possibilities for atherosclerosis, as recombinant interleukin 10 is already being used to treat certain diseases.

These results will be published in the next issue of Circulation Research, through a " fast-track " procedure created for especially important research findings. Only the abstract will figure in the printed version of the journal, the rest of the article being accessible via the Internet.



Institut National de la Santé et de la Recherche Médicale - Tolbiac (INSERM)