Myeloid-related protein 8/14 : a marker of plaque and patient vulnerability

Atherosclerosis, “a disease as old as the mankind”, it remains the first malignancy of the Modern World with a high morbidity and mortality in the elderly. Annually, 12 million deaths in the world caused by the complications of atherosclerotic artery disease (e.g. cerebral stroke and acute myocardial infarction) despite considerably improvements reached in the clinical decisions and treatment of these patients. In the latest decennium, the field witnessed a slight deviation from the standard focus on the pathology of the vulnerable plaque towards a broader approach, the identification of the vulnerable patient. Along with intensive research on the pathobiology of atherosclerosis, research strategies are directed towards the discovery of potential (bio) markers for imaging applications or for screening of patients at high risk for cardio-vascular diseases. The biobank Athero-Express is a good platform when researcher wants to perform studies on both the vulnerable plaque and the vulnerable patient. Myeloid-related protein (Mrp) 8 and 14, also known as S100A8 and S100A9, are two calcium binding proteins mainly expressed in cells of myeloid origin, particularly in monocytes and neutrophils. Both proteins are secreted by activated monocytes and neutrophils and have pro-inflammatory effects. Upon cell activation, the two proteins form a complex, Mrp-8/14, that translocates to the cytoskeleton and plasma membrane where it is secreted. Intracellular, Mrp-8 and Mrp-14 essentially regulate phagocyte (monocytes and neutrophils) migration by integrating the calcium and mitogen-activated protein kinase (MAPK) transduction pathways, thereby controlling reorganization of the phagocyte microtubular system. The secreted Mrp-8/14 complex exerts antimicrobial activity, stimulates IL-8 production by airway epithelial cells, and transports arachidonic acid to endothelial cell (EC) targets affecting pathological responses in inflammation and atherosclerosis. Mrp-8, -14 and -8/14 are expressed in both mouse and human atherosclerotic plaques. Mrp-14 and Mrp-8 are expressed by subsets of macrophages during inflammation in different tissues, as well as in atherosclerotic lesions. The current thesis describes the association of Mrp-8, -14 and -8/14 levels in plaque and plasma with both the atherosclerotic plaque phenotype and secondary cardiovascular events after carotid atherectomy. Additionally, it provides evidence for the expression of Mrps by subsets of plaque macrophages and by plaque neutrophils. Plaque foam macrophages lack Mrp-expression while the Mrp-expressing macrophages lack the morphology of foam cells (in vivo and in vitro). Plaque neutrophils express Mrp-8, -14 and -8/14 and populate in high numbers the vulnerable plaques and in a lower extend the stable plaques