Plasminogen activator inhibitor type 1 in ischemic cardiomyopathy.

Abstract

Plasminogen activator inhibitor type 1 (PAI-1) is a proteinase inhibitor1 constituting the key regulator2 of the activity of the fibrinolytic system, an important protective mechanism against thrombosis. Because a reduced fibrinolytic activity, mainly caused by increased plasma levels of PAI-1, was a common finding in cross-sectional studies of patients with coronary artery disease (CAD),3 high PAI-1 levels have been regarded as a risk factor for recurrent myocardial infarction (MI).4 5 6 It has also been proposed that a reduced fibrinolytic activity may have a role in atherosclerotic plaque formation and in a prothrombotic state, carrying an increased risk of arterial occlusion. Accordingly, over the last few years, several studies have been performed to investigate the role of plasma PAI-1 levels in the development of CAD and MI. Moreover, the observation that polymorphisms of the PAI-1 gene exist, some of which apparently associated with increased plasma PAI-1 levels, stimulated studies aiming at investigating the potential relation between PAI-1 genotypes and ischemic cardiomyopathy. Thus, we shall focus on recent advances in the knowledge of the role of PAI-1 and its gene in the development of ischemic cardiomyopathy. Intravascular fibrinolytic activity results from a balance between plasminogen activators, such as the tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and inhibitors, such as PAI-1 and α2-antiplasmin. PAI-1 is a glycoprotein with a molecular mass of ≈54 kDa that belongs to the serine protease inhibitor superfamily (serpins). Its primary structure was deduced from the sequence of its cDNA.7 It is considered the major physiological inhibitor of t-PA and urokinase, because plasmin formation and fibrinolysis, as well as formation of other extracellular proteases, strongly depend on PAI-1 levels.8 Although the principal source of plasma PAI-1 is unknown, available evidence indicates that several cell types, including endothelial and vascular …