Now a group from the Bristol Heart Institute, University of Bristol, found that specific changes in gene activity contribute to the process. One of these changes, in particular, increases the production of an enzyme that appears to be directly involved in plaque instability.
The discovery, which was presented yesterday, Dec. 11th, by Graciela B. Sala-Newby during the opening lecture of the Third European Vascular Genomics Network (EVGN) Congress (www.evgn.org) in Toulouse (December 11th to 14th), opens up promising perspectives for the treatment of atherosclerosis, suggesting novel targets to slow down and possibly prevent plaque rupture.
The role of macrophages in atherosclerosis is quite complex and also controversial. These cells take part in the formation of the fibrous cap, a layer of connective tissue composed of cells and collagen; but they also promote plaque rupture. [Plaques are made of lipid, cells and extracellular matrix that accumulate in the vessel wall thus obstructing the blood flow: if they become unstable they undergo surface erosion and release tiny fragments – or thrombi - that clog the vessel lumen, leading to myocardial infarction and stroke.] For this reason, the identification of a trigger that switches the process from cap formation to plaque instability was a long-sought goal for scientists.
“We hypothesised that the conversion of macrophages into foam cells (FCM) could be due to genetic changes that up- or down- regulate the amount of proteins produced within these cells” explains Sala-Newby. To test this idea the scientists generated in vivo the two cell types and analyzed their gene expression profile. In other words, they quantified the level of activity of specific genes confirming that the corresponding proteins were more/less produced. “Not surprisingly – says the EVGN scientist – we observed that 3 genes are up-regulated (and their proteins overexpressed) in FCM but not in macrophages, and that 11 genes are down-regulated. When we examined the plaque content we found the same situation”.
One of the overly active genes in the FCM produces the enzyme Metalloproteinase-12 (MMP-12), which, as suggested by Sala-Newby, could become a suitable target for future therapies. “MMP-12 is particularly abundant in the deeper layers of the plaques, and its presence strongly correlates with their instability. Finding the way to inhibit its production would give us a useful tool to counteract plaque rupture”.
Poor expression of some genes proved to be critical as well: according to the scientists, the lack of the enzyme arginase which was observed in FCM, for example, is likely to favour matrix degradation and cellular suicide or apoptosis. “Arginase is a natural competitor of Nitric Oxide” comments Sala-Newby. “Its scarcity leads to the increased production of NO by foam cells, and this in turn generates a harmful environment”.
By convening over 130 leading scientists involved in the study of atherosclerosis - a disease that causes about 50% of deaths in Europe (more than cancer) with a burden of 3 billion Euros for direct and indirect costs - the four-days EVGN Conference presents the state-of-the-art in the post-genomics and proteomics research of Cardiovascular Disease.
The Conference is supported by an unrestricted educational grant from Laboratoires SERVIER.
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