STRUCTURE OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 (PAI-1) AND ITS FUNCTION IN FIBRINOLYSIS - AN UPDATE

Recent evidence has certified that plasminogen activator inhibitor 1 (PAI-1) is a major regulatory protein of the fibrinolytic system in vivo. It rapidly inactivates both tissue-type (t-PA) and urokinase-type plasminogen activator (u-PA). PAI-1 belongs to the serine protease inhibitor ('serpin') superfamily of homologous proteins, X-ray diffraction analysis on crystals of several active and inactive serpins (e.g. PAI-1) has taught us essential features of the three-dimensional structure of these molecules, Moreover, it has provided a rationale for the mechanism of action and for the instability of PAI-1 in the absence of a carrier protein, such as vitronectin. This review summarizes data on the PAI-1 gene and describes the structure and function of the PAI-1 protein. In addition to its interaction with t-PA and u-PA, PAI-1 can efficiently inhibit thrombin in the presence of either vitronectin or the glycosaminoglycan heparin, The mode of interaction of PAI-1 with these cofactors and the localization of the various binding sites are delineated. In addition, the significance of the binding of PAI-1 to intact fibrin for the mechanism of t-PA-mediated fibrinolysis will be outlined. Finally, the role of PAI-1 in vivo will be illustrated by data from recent clinical studies and by observations derived from models with transgenic mice that either overexpress or lack PAI-1. Opportunities for the prevention of reocclusion after thrombolytic treatment of patients, suffering from acute myocardial infarction, by interfering with PAI-I activity will be discussed and may further stimulate research in PAI-1 biology.