Dousing the flames
Arteriosclerosis results from a persistent inflammatory response in the blood vessel wall that begins with the buildup of cholesterol.. These deposits are infiltrated by the immune system’s waste disposal squad, the macrophages, which can provoke a full-blown inflammatory response. Inflammation promotes further growth of the lesions, and obstruction of the vessel may induce a heart attack. A research team led by LMU’s Professor Andreas Schober has now shown, in an animal model, that the inflammation process can be attenuated by knocking out a specific microRNA (miR).
MicroRNAs are derived from stretches of the genome that until recently were regarded as “junk DNA”. It now turns out that within these “gene deserts” the instructions for the synthesis of large numbers of molecular switches reside, including miRs, which play key roles in regulating gene expression in all cells. Thus, miRs have been found to have important functions in cells of the immune system, whose behavior must be rapidly adjusted to changing conditions.
The inhibitor inhibited
Schober’s team studied a mouse model for arteriosclerosis in which some miRs are expressed at high levels in macrophages. They identified miRNA-155 as the most prominent of these short RNAs. “We then wanted to know whether this molecule is directly involved in controlling the pro-inflammatory activity of the macrophages and, if so, how it works,” says Schober. The team discovered that miRNA-155 acts to inhibit the production of one particular protein in the cells.
The target of miRNA-155 was identified as BCL6, an anti-inflammatory protein. In the presence of miRNA-155, the synthesis of BCL6 is severely impaired, and the inflammation runs out of control. The team went on to examine mice that lacked the gene for miRNA-155 in their macrophages. In these cells BCL6 should be present in comparatively high levels, because the inhibitor is missing.
The results were very clear-cut. “In these animals, the extent of arteriosclerosis was markedly reduced,” says Schober. “The incidence of spontaneous heart attacks in mice is low, so we were unable to study how it is affected.” However, the researchers did confirm that miRNA-155 levels are increased in human arteriosclerotic plaques, similar as in mice. This indicates that the miRNA-155 may also promote arteriosclerosis in humans. .
“I am confident that arteriosclerosis in humans can be treated by inhibiting miRs,” says Schober. “Synthetic inhibitors are available for all microRNAs but, of course, they must be extensively tested before they can be used for therapy.” So there’s still a lot of work to be done, not least for Schober’s own laboratory. They now plan to investigate whether miRNA-155 is also involved in metabolic syndrome, a condition that is characterized by overweight, diabetes, high levels of lipids in the circulation and high blood pressure, in addition to an increased risk for heart attacks. (Journal of Clinical Investigation, 8. October 2012) bd/suwe