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Quantitative proteomics comparing human plaque phenotypes

Final Activity Report Summary - PROSTUNST (Quantitative proteomics comparing human plaque phenotypes)

Cardiovascular diseases (CVD) caused 51 % of deaths in Europe in 2001. Coronary heart disease and stroke, which result from atherosclerosis, constitute 80 % of CVD. Better prevention and treatments have halved age-specific incidence, but the ageing population and adverse trends in obesity and diabetes severely threaten these improvements. Future advances in the care of CVD patients depend on developing entire new strategies that are specifically aimed at the early identification of patients at risk for developing complications resulting from atherosclerosis.

The classical concept describes the development of an atherosclerotic plaque towards a large fat component separated from the blood with a thin fibrous cap and a lot of inflammatory cells that produce proteins that breakdown the cap. Rupture of the cap leads to thrombus formation that immediately occludes the artery and leads to a myocardial infarction when this happens in the heart and a stroke when this happens in the brain.

Using a biobank with human atherosclerotic plaque material of 1 200 patients and clinical follow up gave the unique opportunity to discover new markers in these atherosclerotic plaques related to clinical events in the tissue of the event, independent of plaque phenotype. This reduces the size of the haystack dramatically to find the needle and identifies plaque proteins associated with future cardiovascular events and will look at the vulnerable plaque concept from a different angle.

To identify which proteins are related to the vulnerable plaque and which are related to future events (myocardial infarction and stroke), the 'Quantitative proteomics comparing human plaque phenotypes' (PROSTUNST) project developed a proteomics approach for these biobank atherosclerotic plaques in Singapore. This showed a large number of differential expressed plaque proteins between pools of events and controls and between stable and vulnerable plaques. In the Netherlands, protein lists were analysed focussing on the events versus control list. Based on results of proteomics data between myocardial infarction patients and controls, protein identification, differential expression, relations between the proteins and known roles in the cardiovascular system, we selected 15 proteins for verification in the individual patients (appoximately 900) using ELISA and Western. The first protein of these 15 proteins showed a very strong correlation with events but only a moderate correlation with the vulnerable plaque phenotype. Other five ongoing proteins seem to confirm this.

In conclusion, a proteomics approach was established, using a large human atherosclerotic plaque biobank and plaque proteins were identified that relate to future cardiovascular events but have only a moderate relation with plaque phenotype. This shows that plaque phenotype (the classical vulnerable plaque concept) does not the completely describe the process towards an event but that also the protein content and therefore ongoing biological processes determines if an events occurs or not. Also very important, the proteins can be used as biomarkers and image marker to stratify the patient at risk and are potential targets to intervene in this pathology.