ABSTRACT
Atherosclerosis is defined as the accumulation of excess lipid, foam cells, and connective tissue in the arterial intima [1]. One of the earliest steps is the ingress of inflammatory cells through the junctional complexes of activated endothelial cells (ECs), which may require tightly regulated proteolysis [2]. Subsequent movement of inflammatory cells into the deeper layers of the intima and media also requires proteolysis of extracellular matrix (ECM) [3] to remove physical barriers and release latent factors, such as chemo-attractants [4]. Proteolysis of LDL can promote uptake into macrophages and, therefore, aid foam-cell formation [5]. The ability of foam cells not
only to migrate but also to proliferate or undergo apoptosis is also regulated in part by proteolysis [6]. Migration of foam cells to the base of lesions and their subsequent apoptosis and necrosis are key events in generating the lipid pool of atherosclerotic plaques [7]. Proteolysis of the ECM plays a major role in liberating vascular smooth muscle cells (VSMC) from their normal quiescent, contractile state and promoting modulation to a more synthetic phenotype [8]. These modified VSMCs are capable of moving, proliferating, and synthesizing ECM components to build up a fibrous cap over the lipid cores of advanced atherosclerotic plaques. However, VSMCs also have an increased propensity to secrete extracellular proteinases and to undergo apoptosis, which promotes thinning of plaque caps and generation of acellular connective tissue [9]. Proteolysis of such acellular ECM, which has little chance of resynthesis, may be an important trigger for plaque rupture, which precipitates the majority of myocardial infarctions [10]. Detachment of ECs from the ECM, most likely the results of proteolysis, may lead to “endothelial erosion,” the cause of most of the remaining myocardial infarctions [10]. Hence extracellular proteolysis appears to be a proximal cause of acute coronary syndromes and an attractive target for therapeutic intervention. However, designing therapies demands clear identification of the proteinase involved and development of clinically useful inhibitors. Progress towards these aims is discussed below for one family of extracellular proteinases, the matrix degrading metalloproteinases (MMPs) also known as matrixins [4].
