Abstract
Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is a member of the serine protease inhibitor (SERPIN) superfamily and the predominant physiologic inhibitor of urokinase (uPA) and tissue-type (tPA) plasmingen activators. This system effectively restricts, both spatially and temporally, the conversion of plasminogen to plasmin, thereby regulating physiologic and pathophysiologic stromal remodeling. Dysregulation of this cascade frequently results in anomalies of the tissue repair response. Elevated PAI-1 levels are a causative factor in various forms of vascular disease and tissue fibrotic syndromes. Independent of its role in proteolysis, PAI-1 stimulates cell motility via interacting with low-density lipoprotein receptor-related protein-1 (LRP1) activating several cellular signaling pathwaays. PAI-1 also regulates the availability of cell-surface integrins by promoting their endocytosis in an LRP-1- dependent manner via PAI-1/uPA/uPAR (uPA receptor)/LRPI/integrin complexes. This process fine tunes the special control of pericellular proteolysis and the overall cadence of cell detachment/re-adhesion required for efficient cell migration. These data suggest that PAI-1 modulates cell motility under several contexts, both via by its established anti-proteolytic properties and as a signaling initiator.
Highlights
Plasminogen activator inhibitor-1 (PAI-1; SERPINE1), a clade E1 member of the serine protease inhibitor (SERPIN) superfamily, is a major inhibitor of urokinase and tissuetype plasminogen activators
Null (ApoE−/−) mice had a 3-fold up-regulation in plasma and smooth muscle cell PAI-1 mRNA in advanced atherosclerotic lesions compared to wild-type controls [41] suggesting a role in disease progression (e.g., Figure 2)
Since atherogenesis involves lipid accumulation, persistent inflammation, vascular injury, fibrin as well as extracellular matrix (ECM) deposition, elevated PAI-1 expression and its major tissue injury-associated inducer TGF-⊠1 [3,46] it is likely the atherosclerotic response will vary as a function of vascular site, blood flow mechanics, type of injury, tissue levels of PAI-1 and TGF-β1, plaque vulnerability, genetic background and other disease cofactors
Summary
Plasminogen activator inhibitor-1 (PAI-1; SERPINE1), a clade E1 member of the serine protease inhibitor (SERPIN) superfamily, is a major inhibitor of urokinase (uPA) and tissuetype (tPA) plasminogen activators. Inhibition of the fibrinolytic system by PAI-1 overexpression, has been implicated in various pathologies including tissue fibrosis, metabolic disorders and cardiovascular disease (i.e., atherosclerosis, vessel stenosis). Null (ApoE−/−) mice had a 3-fold up-regulation in plasma and smooth muscle cell PAI-1 mRNA in advanced atherosclerotic lesions compared to wild-type controls [41] suggesting a role in disease progression (e.g., Figure 2).
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