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National Institute of Environmental Health Sciences

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Publication Detail

Title: Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis.

Authors: Beier, Juliane I; Kaiser, J Phillip; Guo, Luping; Martinez-Maldonado, Manuel; Arteel, Gavin E

Published In Arch Biochem Biophys, (2011 Jun 1)

Abstract: PAI-1 has been shown to be both profibrotic and antifibrotic in animal models of hepatic fibrosis. Although these models have similarities to human fibrotic liver disease, no rodent model completely recapitulates the clinical situation; indeed, transaminase values in most models of hepatic fibrosis are much higher than in chronic liver diseases in humans. Here, wild-type and PAI-1(-/-) mice were administered AngII (500 ng/kg/min) for 4 weeks. ECM accumulation was evaluated by Sirius red staining, hydroxyproline content, and fibrin and collagen immunostaining. Induction of pro-fibrotic genes was assessed by real-time RT-PCR. Despite the absence of any significant liver damage, AngII infusion increased the deposition of hepatic collagen and fibrin ECM, with a perisinusoidal pattern. PAI-1(-/-) mice were protected from these ECM changes, indicating a causal role of PAI-1 in this fibrosis model. Protection in the knockout strain correlated with a blunted increase in ýýSMA, and elevated activities of matrix metalloproteinases (MMP2, MMP9). These data suggest that PAI-1 plays a critical role in mediating fibrosis caused by AngII and lends weight-of-evidence to a pro-fibrotic role of this protein in liver. Furthermore, the current study proposes a new model of 'pure' hepatic fibrosis in mice with little inflammation or hepatocyte death.

PubMed ID: 21501583 Exiting the NIEHS site

MeSH Terms: Angiotensin II/administration & dosage; Angiotensin II/immunology*; Animals; Collagen/immunology; Extracellular Matrix/immunology; Extracellular Matrix/metabolism; Gene Deletion; Humans; Liver Cirrhosis/genetics*; Liver Cirrhosis/immunology; Liver Cirrhosis/pathology; Liver Cirrhosis/prevention & control*; Liver/immunology; Liver/metabolism; Liver/pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1/genetics*

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