Role of Matrix Metalloproteinases in Atherosclerosis: Pathophysiological and Therapeutic Implications

Atherosclerosis continues to cause considerable morbidity and mortality in the Western countries. In response to cardiovascular risk factors, a cascade of compensatory structural events occurs within the vessel wall. It has become increasingly evident that significant alterations in the structure and composition of the extracellular matrix (ECM) play a key role in the atherogenic process. Far from being a static structure, ECM is a dynamic interactive milieu undergoing continuous remodeling that critically influences cell functions. The activity of proteolytic enzymes is the rate-limiting step in ECM degradation. It is now well established that among numerous other proteinases, the matrix metalloproteinases (MMPs) play the major role in the degradation of collagen and other ECM components. Expressed at low levels in normal adult tissue, MMPs are upregulated in physiological and pathological remodeling processes. MMPs are specialized enzymes involved in processes such as wound healing, but there is growing interest focusing on a pathological role for MMPs in vascular disease states. MMPs are a family of zinc-dependent proteases produced by a variety of cell types, including endothelial, smooth muscle cells (SMC), and monocytes. They are classified into subgroups based upon substrate specificity and/or structure, including collagenases (MMP-1,-8,-13,-18), stromelysins (MMP-3,-10,-11), gelatinases (MMP-2, -9), and the membrane-type MMPs (MT-MMPs). MMP activity is tightly regulated at both intracellular and extracellular levels. Growth factors, cytokines, hormones, and tumor promoters regulate MMP expression at the transcriptional level, while heparin, transforming growth factor-β (TGB-β), and corticosteroids have an inhibitory effect. Extracellular activation of the latent proenzymes represents a second level of control. The major physiological activator of MMPs is plasmin, which activates pro-MMPs to active MMPs (Figure). A further level of control of MMP activity involves the binding of MMPs to specific tissue inhibitor of metalloproteinases (TIMPs). At least four members of TIMP gene family are known: TIMP-1,-2,-3, and -4, all shearing structural features. TIMPs inhibit MMPs by binding irreversible to the active form of the enzyme. Overall, proteolytic activity depends on the relative concentration of the active enzymes and their inhibitors.