Abstract
Plasminogen activator inhibitor type 1 (PAI-1) is the main physiologic inhibitor of fibrinolysis. However, it is also involved in many physiological processes such as extracellular matrix (ECM) proteolysis and remodeling, cell adhesion, motility, and apoptosis, angiogenesis, etc. The aim of the study was to summarize current knowledge and gain insights into the mechanisms of PAI-1 action in the processes of stromal remodeling and diseases with considerable matrix pathologies (atherosclerosis, tissue fibrosis, cancer metastasis, pregnancy related complications, etc). As a component of an early cellular response to injury, PAI-1 reacts with membrane surface proteins and participates in the initiation of intracellular signaling, specifically cytoskeletal reorganization and motility. Complexity of ECM homeostasis resides in varying relation of the plasminogen system components and other matrix constituents. Inflammatory mediators (transforming growth factor-β and interferon-γ) and hormones (angiotensin II) are in the close interdependent relation with PAI-1. Also, special attention is devoted to the role of increased PAI-1 concentrations due to the common 4G/5G polymorphism. Some of the novel mechanisms of ECM modification consider PAI-1 dependent stabilization of urokinase mediated cell adhesion, control of the vascular endothelial cadherin trafficking and interaction with endothelial cells proteasome, its relation to matrix metalloproteinase 2 and osteopontin, and oxidative inhibition by myeloperoxidase. Targeting and/or alteration of PAI-1 functions might bring benefit to the future therapeutic approaches in diseases where ECM undergoes substantial remodeling.
Highlights
Plasminogen activator inhibitor type 1 (PAI-1) is a multifunctional protein involved in a number of physiologic processes, where it may exhibit its procoagulant, antiadhesive, proinflammatory, profibrotic orproteolytic effects
The function of PAI-1 is not restricted to the inhibition of intravascular fibrinolysis but is important in a vast number of tissue remodeling processes that involve cell motility and their interactions with extracellular matrix (ECM)
PAI-1 is a component of early cellular response to injury and by reacting with membrane surface proteins it participates in cell adhesion and initiation of intracellular signaling, cytoskeletal reorganization
Summary
Plasminogen activator inhibitor type 1 (PAI-1) is a multifunctional protein involved in a number of physiologic processes, where it may exhibit its procoagulant, antiadhesive, proinflammatory, profibrotic or (anti)proteolytic effects. It is the main physiologic inhibitor of fibrinolysis; tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA or urokinase). Through its effects on PAs, PAI-1 regulates plasmin and matrix metalloproteinases (MMP) activity and tissue homeostasis[1,2,3]. PAI-1 interaction with other proteins can stabilize its active conformation and prolong activity. The aim of the study was to summarize current knowledge and gain insights into the mechanisms of PAI-1 action in the processes of stromal remodeling and diseases with considerable matrix pathologies
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