Plasmin plays a key role in the regulation of profibrogenic molecules in hepatic stellate cells

  1. Abril Martínez-Rizo1,
  2. Miriam Bueno-Topete1,
  3. Jaime González-Cuevas1,
  4. Juan Armendáriz-Borunda1,2

Article first published online: 2 NOV 2009

DOI: 10.1111/j.1478-3231.2009.02155.x

Issue

Liver International

Liver International

Volume 30, Issue 2, pages 298–310, February 2010

Additional Information

How to Cite

Martínez-Rizo, A., Bueno-Topete, M., González-Cuevas, J. and Armendáriz-Borunda, J. (2010), Plasmin plays a key role in the regulation of profibrogenic molecules in hepatic stellate cells. Liver International, 30: 298–310. doi: 10.1111/j.1478-3231.2009.02155.x

Author Information

  1. 1

    Department of Molecular Biology and Genomics, CUCS, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, Guadalajara, Jalisco, Mexico

  2. 2

    OPD Hospital Civil de Guadalajara, University of Guadalajara, Guadalajara, Jalisco, Mexico

*Correspondence Dr Juan Armendáriz-Borunda, Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, U de G, Apdo. Postal 2-123, Guadalajara, Jalisco, México 44281 Tel: +52 33 10 58 53 17 Fax: 52 33 10 58 53 18 e-mail: armdbo@gmail.com

Publication History

  1. Issue published online: 23 DEC 2009
  2. Article first published online: 2 NOV 2009
  3. Received 18 August 2009Accepted 21 September 2009

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Keywords:

  • adenovector;
  • aprotinin;
  • fibrogenesis;
  • hepatic stellate cells;
  • plasmin;
  • tranexamic acid;
  • urokinase plasminogen activator

Abstract

Background: Plasmin role in transforming growth factor-β (TGF-β)-responsive gene regulation remains to be elucidated. Also, plasmin action on co-repressor Ski-related novel protein N (SnoN) and differential activation of matrix metalloproteinases (MMPs) are unknown. Thus, the role of plasmin on profibrogenic molecule expression, SnoN transcriptional kinetics and gelatinase activation was investigated.

Methods: Hepatic stellate cells (HSC) were transduced with adenovirus-mediated human urokinase plasminogen activator (Ad-huPA) (4 × 109 viral particles/ml). Overexpression of urokinase plasminogen activator and therefore of plasmin, was blocked by tranexamic acid (TA) in transduced HSC. Gene expression was monitored by reverse transcriptase polymerase chain reaction. HSC-free supernatants were used to evaluate MMP-2 and MMP-9 by zymography. SnoN, TGF-β and tissue inhibitor of metalloproteinase (TIMP)-1 were analysed by Western blot. Plasmin and SnoN expression kinetics were evaluated in bile duct-ligated (BDL) rats.

Results: Plasmin overexpression in Ad-huPA-transduced HSC significantly decreased gene expression of profibrogenic molecules [α1(I)collagen 66%, TIMP-1 59%, α-smooth muscle actin 90% and TGF-β 55%]. Interestingly, both SnoN gene and protein expression increased prominently. Plasmin inhibition by TA upregulated the profibrogenic genes, which respond to TGF-β-intracellular signalling. In contrast, SnoN mRNA and protein dropped importantly. Plasmin-activated MMP-9 and MMP-2 in HSC supernatants. Taken together, these findings indicate that MMP-9 activation is totally plasmin dependent. SnoN levels significantly decreased in cholestatic-BDL rats (82%) as compared with control animals. Interestingly, hepatic plasmin levels dropped 46% in BDL rats as compared with control.

Conclusion: Plasmin plays a key role in regulating TGF-β-responding genes. In particular, regulation of TGF-β-co-repressor (SnoN) is greatly affected, which suggests SnoN as a cardinal player in cholestasis-induced fibrogenesis.

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