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The gene dance that promotes atherosclerosis

University Of Bristol : 06 March, 2006  (Technical Article)
Hardening of the arteries, atherosclerosis, is a common disorder which occurs when fat, cholesterol and other substances build up in the walls of arteries and form hard substances called plaque. A discovery by Dr Graciela Sala-Newby and colleagues at the Bristol Heart Institute could lead to new ways of treating this condition which is responsible for almost half of all deaths in Europe.
Among the key factors in the onset and progression of atherosclerosis is the conversion of cells called macrophages into ‘foam cells’ whose presence is associated with plaque instability.

Until recently, scientists had little information about the genetic events behind this transformation. Now, researchers at the Bristol Heart Institute have 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 by Dr Sala-Newby during the opening lecture of the Third European Vascular Genomics Network Congress in Toulouse, 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 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 lumen (the central space in an artery) 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.

Dr Sala-Newby and colleagues hypothesised that the conversion of macrophages into foam cells could be due to genetic changes that up, or down, regulate the amount of proteins produced within these cells. To test this idea, they 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 or less produced.

Not surprisingly, they observed that three genes are up-regulated (and their proteins overexpressed) in FCM but not in macrophages, and that 11 genes are down-regulated. When they examined the plaque content, they found the same situation.

One of the overly active genes in the FCM produces the enzyme Metalloproteinase-12, which 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 provide 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. Its scarcity leads to the increased production of nitric oxide by foam cells and this in turn generates a harmful environment.

The European Vascular Genomics Network Conference
By convening over 130 leading scientists involved in the study of atherosclerosis – a disease that causes about 50 per cent of deaths in Europe (more than cancer) with a burden of 3 billion Euros for direct and indirect costs, the four-day EVGN Conference presents state-of-the-art post-genomics and proteomics research of Cardiovascular Disease.

The European Vascular Genomics Network is the first Network of excellence on cardiovascular disease funded by the European Commission under the 6th Framework Programme ‘Life sciences, genomics and biotechnology for health’.
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