Molecular interactions between the plasminogen/plasmin and matrix metalloproteinase systems

Abstract

Abstract Circumstantial evidence suggests an important role of the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems in biological processes involving (extra)cellular proteolysis and matrix degradation. The availability of mice with inactivation of main components of both systems has allowed to study directly the interactions between both systems and their biological role. In purified system, MMP-3 (stromelysin-1) specifically hydrolyzes plasminogen and urokinase-type plasminogen activator (u-PA), thereby removing the cellular binding domains from both proteins. In the presence of cells, MMP-3 may downregulate cell-associated plasmin activity by decreasing the amount of activatible plasminogen, without affecting cell-bound u-PA activity. During neointima formation after vascular injury in gene-deficient mice, expression of MMP-2 and MMP-9 (gelatinase A and B) is strongly enhanced, independently of the presence or absence of plasminogen or of the physiological plasminogen activators. Activation of proMMP-2 occurs independently of plasmin, whereas proMMP-9 activation occurs via plasmin-dependent as well as plasmin-independent mechanisms. The temporal and topographic expression patterns of MMP-2, MMP-3, MMP-9, MMP-12 (metalloelastase) and MMP-13 (collagenase) establish a potential role in neointima formation. This is further substantiated by the finding that neointima formation after vascular injury is significantly enhanced in mice with deficiency of TIMP-1, a main physiological MMP inhibitor. Atherosclerosis models in gene-deficient mice suggest an important role of u-PA in the structural integrity of the atherosclerotic vessel wall. u-PA-mediated plasmin generation may contribute to activation of latent MMPs (MMP-3, -9, -12, and -13) which degrade insoluble elastin and fibrillar collagen. Thus, studies with gene-deficient mice have allowed to establish novel interactions between the fibrinolytic and MMP systems, which may play a role in biological processes requiring cellular proteolytic activity and/or extracellular matrix degradation.