Small Molecule Targeting of PAI-1 Function: A New Therapeutic Approach for Treatment of Vascular Stenosis

Simone, Tessa M.; Archambeault, Jaclyn; Higgins, Paul J.

doi:10.4172/1747-0862.1000059

Cited by 3 publications

(2 citation statements)

References 31 publications

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“…Several studies have shown that PAI-1 deficiency is associated with a reduced tissue fibrosis. Inhibitors of PAI-1 such as small molecules and siRNA ameliorate organ fibrosis [Meryet-Figuieres et al, 2007;Hu et al, 2009;Simone et al, 2013;Ghosh et al, 2016].…”

Section: Perturbation Of Pai-1 Levels and Tissue Fibrosismentioning

confidence: 99%

Plasminogen Activator Inhibitor Type‐1 as a Regulator of Fibrosis

Rabieian

Boshtam

Zareei

et al. 2017

J of Cellular Biochemistry

150

140

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Fibrosis is known as a frequent and irreversible pathological condition which is associated with organ failure. Tissue fibrosis is a central process in a variety of chronic progressive diseases such as diabetes, hypertension, and persistent inflammation. This state could contribute to chronic injury and the initiation of tissue repair. Fibrotic disorders represent abnormal wound healing with defective matrix turnover and clearance that lead to excessive accumulation of extracellular matrix components. A variety of identified growth factors, cytokines, and persistently activated myofibroblasts have critical roles in the pathogenesis of fibrosis. Irrespective of etiology, the transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. Overexpression of PAI-1 reduces extracellular matrix degradation via perturbing the plasminogen activation system. Indeed, elevated PAI-1 levels inhibit proteolytic activity of tissue plasminogen activator and urokinase plasminogen activator which could contribute to a variety of inflammatory elements in the injury site and to excessive matrix deposition. This review summarizes the current knowledge of critical pathways that regulate PAI-1 gene expression and suggests effective approaches for the treatment of fibrotic disease. J. Cell. Biochem. 119: 17-27, 2018. © 2017 Wiley Periodicals, Inc.

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Section: Perturbation Of Pai-1 Levels and Tissue Fibrosismentioning

confidence: 99%

Plasminogen Activator Inhibitor Type‐1 as a Regulator of Fibrosis

Rabieian

Boshtam

Zareei

et al. 2017

J of Cellular Biochemistry

150

140

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“…microRNA (miRNA)-181b, a member of the miRNA-181 family, has been revealed to be involved in the proliferation, invasion and apoptosis of tumor cells that are associated with tumor invasiveness ( 2 , 3 ). Plasminogen activator inhibitor-1 (PAI-1), a novel target for the clinical treatment of cardiovascular disease ( 4 ), inhibits fibrinolysis, induces barriers for extracellular matrix degradation, impacts the invasiveness of cells ( 5 ) and plays an important role in vascular structural and functional changes ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Levels of microRNA-181b and plasminogen activator inhibitor-1 are associated with hypertensive disorders complicating pregnancy

Yan-shan

Shen

et al. 2014

Experimental and Therapeutic Medicine

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The aim of the present study was to explore the association between the expression of microRNA (miRNA)-181b and plasminogen activator inhibitor-1 (PAI-1) in the placental tissue of pregnant females with a hypertensive disorder complicating pregnancy (HDCP). Placental tissue samples were obtained from 48 patients with HDCP and 40 females with a normal pregnancy. The levels of miRNA-181b and PAI-1 mRNA were determined by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of PAI-1 protein was analyzed by western blotting. Vascular smooth muscle cells (VSMCs) were transfected with the pEGP-miRNA-181b plasmid using Lipofectamine® 2000. Transfection efficiency was confirmed by immunohistochemical analysis. The levels of miRNA-181b in the placental tissue of patients with HDCP were lower than those in the control group, whereas the levels of PAI-1 mRNA in the placental tissue of patients with HDCP were higher than those in the control group. The expression of the PAI-1 protein in the HDCP group was higher than that in the control group. Following transfection of VSMCs with plasmid pGCMV/EGFP/miRNA-181b, the levels of PAI-1 mRNA were reduced while the levels of miRNA-181 were upregulated. Furthermore, the expression levels of PAI-1 protein were lower than those in the control group. The levels of miRNA-181b and PAI-1 mRNA were strongly associated with HDCP. Thus, miRNA-181b may play an important role in the regulation of PAI-1. PAI-1 and miRNA-181b may be novel biomarkers to be used in HDCP therapy.

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Targeted Inhibition of PAI-1 Activity Impairs Epithelial Migration and Wound Closure Following Cutaneous Injury

Simone

Longmate

Law

et al. 2015

Advances in Wound Care

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Objective: Aberrant plasminogen activator inhibitor-1 (PAI-1) expression and activity have been implicated in bleeding disorders, multiorgan fibrosis, and wound healing anomalies. This study details the physiological consequences of targeted PAI-1 functional inhibition on cutaneous injury repair. Approach: Dorsal skin wounds from FVB/NJ mice, created with a 4 mm biopsy punch, were treated topically with the small-molecule PAI-1 antagonist tiplaxtinin (or vehicle control) for 5 days and then analyzed for markers of wound repair. Results: Compared to controls, tiplaxtinin-treated wounds displayed dramatic decreases in wound closure and re-epithelialization. PAI-1 immunoreactivity was evident at the migratory front in all injury sites indicating these effects were due to PAI-1 functional blockade and not PAI-1 expression changes. Stimulated HaCaT keratinocyte migration in response to recombinant PAI-1 in vitro was similarly attenuated by tiplaxtinin. While tiplaxtinin had no effect on keratinocyte proliferation, cell cycle progression, or apoptosis, it effectively reduced collagen deposition, the number of Ki-67 + fibroblasts, and incidence of differentiated myofibroblasts (i.e., smooth muscle a-actin immunoreactive cells), but not fibroblast apoptosis. Innovation: The role for PAI-1 in hemostasis and fibrinolysis is established; involvement of PAI-1 in cutaneous wound healing, however, remains unclear. This study tests the effect of a small-molecule PAI-1 inhibitor in a murine model of skin wound repair. Conclusion: Loss of PAI-1 activity significantly impaired wound closure. Reepithelialization and fibroblast recruitment/differentiation were both reduced in tiplaxtinin-treated mice. Therapies directed at manipulation of PAI-1 expression and/or activity may have applicability as a treatment option for chronic wounds and scarring disorders. INTRODUCTIONPlasminogen activator inhibitor-1 (PAI-1; SERPINE1), the major regulator of the pericellular proteolytic and fibrinolytic cascades, is a critical factor in the motile wound repair response in multiple cell lineages. PAI-1 is induced upon keratinocyte injury and restricted to the injury site where it is required for efficient keratinocyte migration in cell culture models of wound healing. [1][2][3] These data are consistent with earlier findings that this SERPIN is among the most highly upregulated genes in the serum-activated wound-healing genomic program. 4,5 Dysregulated PAI-1 expression is a causative factor in aberrant wound healing and fibrosis where Several low-molecular-weight antagonists have been designed to assess the impact of PAI-1 functional inhibition in several in vitro and in vivo models of tissue injury. The well-studied smallmolecule PAI-1 inhibitor, tiplaxtinin (PAI-039), which promotes a substrate-like conformation and PAI-1 cleavage, effectively reduces airway remodeling in an asthmatic mouse model and decreases the extent of hyperlipidemia, hyperglycemia, angiogenesis, and restenosis. 15,16 To determine the requirement for the PAI-1 activity on ...

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Small Molecule Targeting of PAI-1 Function: A New Therapeutic Approach for Treatment of Vascular Stenosis

Cited by 3 publications

References 31 publications

Plasminogen Activator Inhibitor Type‐1 as a Regulator of Fibrosis

Plasminogen Activator Inhibitor Type‐1 as a Regulator of Fibrosis

Levels of microRNA-181b and plasminogen activator inhibitor-1 are associated with hypertensive disorders complicating pregnancy

Targeted Inhibition of PAI-1 Activity Impairs Epithelial Migration and Wound Closure Following Cutaneous Injury

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