Chemical Antagonists of Plasminogen Activator Inhibitor-1: Mechanisms of Action and Therapeutic Potential in Vascular Disease
Tessa M Simone, Stephen P Higgins, Craig E Higgins, Michelle R Lennartz and Paul J Higgins*
Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York 12208, USA
- Corresponding Author:
- Dr. Paul J. Higgins
Center for Cell Biology & Cancer Research
Albany Medical College, 47 New Scotland Avenue
Albany, New York 12208, USA
E-mail: [email protected]
Received date: July 07, 2014; Accepted date: September 16, 2014; Published date: September 21, 2014
Citation: Simone TM, Higgins SP, Higgins CE, Lennartz MR, Higgins PJ (2014) Chemical Antagonists of Plasminogen Activator Inhibitor-1: Mechanisms of Action and Therapeutic Potential in Vascular Disease. J Mol Genet Med 8:125. doi:10.4172/1747-0862.1000125
Copyright: © 2014 PJ Higgins, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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.