Plasminogen activator inhibitor-1: the double-edged sword in apoptosis

Abstract

Plasminogen activator inhibitor type-1 (PAI-1) is a multi-functional protein. It is a fast-acting inhibitor of plasminogen activators; urokinase-plasminogen activator and tissue type plasminogen activator, and also plays an important role in regulating cell proliferation, adhesion, migration, and signal transduction pathways. These biological events are important processes during angiogenesis and restenosis. PAI-1 has been shown to regulate proliferation, migration, and apoptosis of vascular smooth muscle cells and endothelial cells. The ability of PAI-1 to regulate cellular proliferation and migration has been attributed to its ability to control plasmin production, modify signaling pathways, and its inherent multifactorial ability to bind to vitronectin and lipoprotein receptor-related protein. However, the mechanism by which PAI-1 regulates the apoptotic pathway is not well understood. Evidence from the literature suggests that PAI-1 or its deficiency alters key signalling pathways, such as the PI3-k/Akt and the Jak/STAT pathways, and is involved in maintaining endothelial cell integrity thereby regulating cell death. Other investigators have demonstrated that PAI-1 directly binds to caspases as a mechanism of PAI-1-mediated cellular apoptosis. Moreover, results from studies assessing the role of PAI-1 in apoptosis have suggested that PAI-1 can exert pathogenic or protective effects, which may be related to the disease model or type of injury employed.

Figure 1. PAI-1-mediated apoptosis

The exact mechanism of PAI-1-regulated apoptosis is not clear and several different scenarios are possible. The uPA/uPAR/PAI-1 complex (1) in the presence of LRP is endocytosed (2). Intracellular PAI-1 can complex with caspase-3 leading to its inactivation promoting an anti-apoptotic effect (3), while uPAR and LRP are recycled to the cell surface (4). Alternatively, PAI-1 due to its interaction with LRP can transduce signaling intermediates inhibiting apoptosis (5a) by an unknown mechanism or promote survival by up-regulation of the c-jun/ERK pathway and anti-apoptotic proteins Bcl-2, Bcl-X_L(5b). In a PAI-1 deficient state (6) there is sustained Akt activation resulting in increased levels of phosphorylated caspase-9 and increased levels of pro- or inactive caspase-3 promoting an anti-apoptotic state (7). Alternatively, PAI-1 can bind to vitronectin (8) competing with EC integrins and preventing binding of the cell to the matrix causing anoikis.