The Limelight: The Immune Mechanisms Of Atherosclerosis

Scientists are depicting a novel scheme for atherosclerosis development, suggesting that this pathology might result from an imbalance between pro-inflammatory processes and calming ones. This is one of intriguing scientific results that emerge from the Second European Vascular Genomics Network Conference (EVGN Conference – Hamburg, September 27th – 30th 2005). These results provide new insights into the role of inflammation in heart disease and led to development of new informative models of blood clot formation and the processes that lead to heart attacks.

The inflammatory process is a sort of alarm bell that indicates the onset of atherosclerosis. In the recent past it had become clear that both innate and acquired immune responses mediated by white blood cells (inflammation) play a critical role in the development of this pathology. By altering tissue homeostasis (i.e. the whole of the metabolic events that maintain internal equilibrium) the inflammatory process paves the way towards the deposition of early fatty streaks. This event in turn stimulates endothelial activation (the endothelium is the inner lining of blood vessels) favouring the recruitment of infiltrating blood cells.

But what seemed quite a chaotic process turned out to be more organized than previously envisaged. Recently, Alain Tedgui, EVGN scientific coordinator (INSERM (Institut National de la Santé et de la Recherche Médicale, Paris, France) and colleagues have provided evidence that the immuno-inflammatory responses are tightly modulated: among the actors there are two anti-inflammatory cytokines that counter-balance the effects of other pro-inflammatory mediators.

“More specifically” points out Tedgui “these cytokines act upon a sub-population of T-cells (Reporter’s note: T-cells cells normally protect us against invading pathogens) called regulatory T cells (Treg), which were shown to control atherosclerosis in a widely used model mouse”. On this basis, scientists are now depicting a novel scheme for atherosclerosis development, suggesting that this pathology might result from an imbalance between pro-inflammatory T-cells and calming ones, the T reg.

In parallel, studies of human atherosclerotic plaques – and of the mechanisms that trigger their rupture – have made considerable progress during this last year. Göran Hansson from the Center for Molecular Medicine at the Karolinska Hospital, Stockholm, investigated the content of such plaques, finding a link between specific infiltrating cells and the production of inflammatory substances. “The start signal of the whole process depends – explains Hansson – also on the involvement of receptors called Toll-like that recognize some endogenous molecules activating the inflammatory signalling pathways”.

Other research led by Chris Jackson in Bristol developed a new mouse model of unstable atherosclerosis, and Jason Johnson used it to identify both harmful and protective roles for enzymes derived from inflammatory cells that either promote repair of or destroy the strength giving collagen components of atherosclerotic plaques. Clearly tight regulation of these enzymes, called metalloproteinases, is essential to obtain their reparative effects while avoiding the destructive ones stemming from their overactivity.

These and other results, albeit very promising, explain only a small component of the complex pathology of atherosclerosis. More experimental studies are certainly needed before clinical trials can be performed on humans. To aid this EVGN has plans next year to generate 9 original mouse strains to address the roles of other candidate therapeutic genes.

EVGN IN EUROPE

The European Vascular Genomics Network (EVGN) is a network of excellence funded by the European Commission under the 6th Framework Programme (Contract Number: LSHM-CT-2003-503254).

Today, cardiovascular diseases (CVDs) rank higher than in the past in the priorities of the National Health Systems of the EU. In fact they account for more deaths than cancer, which is wrongly considered the most malignant pathology in westernized countries. Every year the consequences of CVDs, for example myocardial infarction and strokes, kill some 19 million people worldwide (5 million people in Europe), exacting a toll of more than 500 billion dollars in terms of healthcare costs and loss of productivity for those who survive.

That’s why biomedical research, in particular Vascular Biology, urgently needs support at national and European levels. Europe-wide collaboration facilitates an interdisciplinary approach such as the one provided by the laboratories that belong to EVGN. Such cooperation is particularly appropriate in a newborn field like genomics; to overcome national skill shortages in recently developed investigation tools such as bioinformatics, high throughput systems, proteomics, transcriptomics and metabolomics.

The second year of EVGN activity has proceeded with restless spirit and enthusiasm. “During 2004-2005 the integration between the EVGN groups working in the three thematic areas of the Network – endothelial dysfunction, plaque instability and therapeutic angiogenesis – has considerably strengthened” confirms Alain Tedgui, EVGN scientific coordinator. “As a result we have achieved excellent scientific productivity, for example in terms of quality publications. Just to mention a few: nine publications from at least two EVGN groups have been published in high ranking journals, including Nature Medicine, Journal of Experimental Medicine, Circulation Research and Circulation”.

This year, the EVGN meeting takes place together with the 3rd European Meeting on Vascular Biology and Medicine (www.emvbm.org)

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