Plasminogen Activator Inhibitor-1

Gils, Ann; Declerck, Paul

doi:10.2174/0929867043364595

Cited by 76 publications

(56 citation statements)

References 153 publications

(233 reference statements)

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“…Among the many renoprotective properties of the AngII inhibitors is their ability to suppress PAI-1. Development of selective anti-PAI-1 therapeutic agents is under way, but the ideal antifibrotic agent has not yet been discovered (145). Much still remains to be disclosed about the role of PAI-1 in CKD.…”

Section: Resultsmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

Eddy

Fogo

2006

Journal of the American Society of Nephrology

211

189

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Section: Resultsmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

Eddy

Fogo

2006

Journal of the American Society of Nephrology

211

189

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“…PAI-1, a member of the serpin superfamily and the major physiological inhibitor of tissue-type plasminogen activator and urokinase plasminogen activator in vivo, decreases both direct and indirect effects of plasmin on extracellular matrix degradation but also decreases plasmin-mediated activation of TGF-␤ and cell migration. 33,34 Thus, whereas PAI-1 contributes to vascular remodeling and renal injury during excess Ang II or aldosterone, 35,36 increased PAI-1 expression protects against cardiac fibrosis, likely by decreasing urokinase-dependent macrophage infiltration. 11,37,38 …”

Section: Activation Of the Raas Contributes To Oxidative Stress And Vmentioning

confidence: 99%

Aldosterone and Vascular Inflammation

2008

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“…This suggests that the tPA/plasmin cascade may be inhibited in AD (17,18). A known inhibitor of this cascade is plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) gene family and the primary inhibitor of tPA and uPA (19,20). Binding of PAI-1 to tPA irreversibly inhibits the serine protease activity of tPA and thus inhibits the conversion of plasminogen to plasmin (19).…”

mentioning

confidence: 99%

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Js¹,

Ta²,

Martone³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

130

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The amyloid hypothesis states that a variety of neurotoxic ␤-amyloid (A␤) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between A␤ production and clearance. Enzymes responsible for the degradation of A␤ are not well understood, and, thus far, it has not been possible to enhance A␤ catabolism by pharmacological manipulation. We provide evidence that A␤ catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain A␤ levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades A␤ oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain A␤. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain A␤ levels, restore long-term potentiation deficits in hippocampal slices from transgenic A␤-producing mice, and reverse cognitive deficits in these mice.Alzheimer ͉ plasminogen activator inhibitor ͉ tissue plasminogen activator A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of intracellular neuronal tangles and extracellular parenchymal and vascular amyloid deposits containing ␤-amyloid peptide (A␤). A␤ is a 39-to 42-aa peptide derived from the proteolytic processing of the amyloid precursor protein (APP) (1). The ''amyloid hypothesis'' of AD postulates a central causal role for A␤ in AD pathogenesis and is supported by genetic and physiological evidence. All known early onset familial AD mutations result in enhanced levels of cytotoxic A␤ species, amyloid plaque deposition, and dementia. Furthermore, A␤ peptide is reported to be neurotoxic and synaptotoxic in vitro and in vivo, inhibiting long-term potentiation (LTP), a physiological correlate of memory (2). Based on these observations, a number of strategies to reduce brain A␤ levels are being pursued as therapeutic approaches to treat AD (3, 4).If the amyloid hypothesis of AD is correct and A␤ levels are pivotal to disease etiology, then the balance between A␤ production and catabolism is likely to be a key determinant of disease progression. It has been suggested that insufficient clearance of A␤ may account for elevated A␤ levels in the brain and the accumulation of pathogenic amyloid deposits in sporadic AD (5). A number of proteases have been implicated in the proteolytic clearance of A␤ from the CNS, including neprilysin, insulin-degrading enzyme, endothelin converting enzyme, and plasmin (3, 6-8). The relative contribution of these enzymes to A␤ catabolism remains unclear, but each protease may play a significant role in the degradation and clearance of A␤, resulting in a slowing of A␤ accumulation and aggregation and u...

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Plasminogen Activator Inhibitor-1

Cited by 76 publications

References 153 publications

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

Aldosterone and Vascular Inflammation

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

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