title: A small molecule PAI-1 functional inhibitor attenuates neointimal hyperplasia and vascular smooth muscle cell survival by promoting PAI-1 cleavage.
abstract: Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of urokinase-and tissue-type plasminogen activators (uPA and tPA), is an injury-response gene implicated in the development of tissue fibrosis and cardiovascular disease. PAI-1 mRNA and protein levels were elevated in the balloon catheter-injured carotid and in the vascular smooth muscle cell (VSMC)-enriched neointima of ligated arteries. PAI-1/uPA complex formation and PAI-1 antiproteolytic activity can be inhibited, via proteolytic cleavage, by the small molecule antagonist tiplaxtinin which effectively increased the VSMC apoptotic index in vitro and attenuated carotid artery neointimal formation in vivo. In contrast to the active full-length serine protease inhibitor (SERPIN), elastase-cleaved PAI-1 (similar to tiplaxtinin) also promoted VSMC apoptosis in vitro and similarly reduced neointimal formation in vivo. The mechanism through which cleaved PAI-1 (CL-PAI-1) stimulates apoptosis appears to involve the TNF-α family member TWEAK (TNF-α weak inducer of apoptosis) and it's cognate receptor, fibroblast growth factor (FGF)-inducible 14 (FN14). CL-PAI-1 sensitizes cells to TWEAK-stimulated apoptosis while full-length PAI-1 did not, presumably due to its ability to down-regulate FN14 in a low density lipoprotein receptor-related protein 1 (LRP1)-dependent mechanism. It appears that prolonged exposure of VSMCs to CL-PAI-1 induces apoptosis by augmenting TWEAK/FN14 pro-apoptotic signaling. This work identifies a critical, anti-stenotic, role for a functionally-inactive (at least with regard to its protease inhibitory function) cleaved SERPIN. Therapies that promote the conversion of full-length to cleaved PAI-1 may have translational implications.
authors.affiliation: Center for Cell Biology & Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, United States. Electronic address: simonet@mail.amc.edu.
authors.forename: Tessa M
authors.initials: TM
authors.lastname: Simone
authors.affiliation: Center for Cell Biology & Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, United States. Electronic address: higgins@mail.amc.edu.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Higgins
authors.affiliation: Center for Cell Biology & Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, United States. Electronic address: archamj@mail.amc.edu.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Archambeault
authors.affiliation: Center for Cell Biology & Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, United States. Electronic address: higginc@mail.amc.edu.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Higgins
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, United States. Electronic address: ginnanr@mail.amc.edu.
authors.forename: Roman G
authors.initials: RG
authors.lastname: Ginnan
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, United States. Electronic address: singer@mail.amc.edu.
authors.forename: Harold
authors.initials: H
authors.lastname: Singer
authors.affiliation: Center for Cell Biology & Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, United States. Electronic address: higginp@mail.amc.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Higgins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016893:Carotid Stenosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005341:Fibrinolysin / Q000378:metabolism; D006965:Hyperplasia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007210:Indoleacetic Acids / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin; D005341:Fibrinolysin
keywords: Apoptosis; Carotid stenosis; PAI-1; SERPIN; Vascular injury