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- Title
Urokinase plasminogen activator stimulates function of active forms of stromelysin and gelatinases (MMP-2 and MMP-9) in cirrhotic tissue.
- Authors
Gonzaleslez-Cuevas, Jaime; Bueno-Topete, Miriam; Armendariz-Borunda, Juan
- Abstract
Background: The authors’ previous data support the notion that adenoviral-driven urokinase plasminogen activator (u-PA) expression results in reversion of experimental liver cirrhosis. The specific aim of the present study was to decipher the mechanisms involved in the regulation by endogenous/gene-delivered u-PA of matrix metalloproteinases (MMP) and related proteins engaged in degradation of excessive hepatic connective tissue. Methods: Tissue slices from cirrhotic rat livers were incubated with u-PA-rich supernatants from 24-h-cultured hepatic stellate cells (HSC). Matrix metalloproteinase-2, -9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) were detected by western blot and biologic activity. The HSC that discontinued u-PA production were transfected with the adenovector Adu-PA and serum-free supernatants evaluated for proteolytic activity by MMP-3, MMP-2 and MMP-9. Collagen I, transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor-1 (PAI-1) and TIMP-1 mRNA levels were also evaluated. Results and Conclusion: Endogenous u-PA from cultured HSC significantly induced the active forms of MMP-2 (68 kDa) and MMP-9 (78 kDa) in cirrhotic tissue slices. The TIMP-1 molecular forms demonstrated that u-PA pushed the presence of ‘free’ TIMP-1 (not complexed with MMP; 71%) in cirrhotic tissue. When non-producing u-PA-HSC were transfected with adenoviral vector coding for the functional human protein u-PA (Adhu-PA), an overactivation of MMP-3, MMP-2 and MMP-9 (800%, 48% and 100%, respectively) was found as compared with HSC transfected with control adenovirus encoding green fluorescent protein (Ad-GFP). Finally, gene expression of collagen I, TGF-β1, PAI-1 and TIMP-1 were downregulated by Adhu-PA action as well.
- Subjects
CIRRHOSIS of the liver; UROKINASE; PLASMINOGEN; METALLOPROTEINASES; LABORATORY rats; TISSUES
- Publication
Journal of Gastroenterology & Hepatology, 2006, Vol 21, Issue 10, p1544
- ISSN
0815-9319
- Publication type
Article
- DOI
10.1111/j.1440-1746.2006.04398.x