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Premium Urokinase plasminogen activator stimulates function of active forms of stromelysin and gelatinases (MMP‐2 and MMP‐9) in cirrhotic tissue
Author(s)
GonzálezCuevas Jaime,
BuenoTopete Miriam,
ArmendarizBorunda Juan
Publication year2006
Publication title
journal of gastroenterology and hepatology
Resource typeJournals
PublisherBlackwell Publishing Asia
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.
Subject(s)biochemistry , biology , connective tissue , fibrinolysis , gene , hepatic stellate cell , matrix metalloproteinase , medicine , microbiology and biotechnology , pathology , plasminogen activator , plasminogen activator inhibitor 1 , t plasminogen activator , tissue plasminogen activator , transfection , urokinase , western blot
Language(s)English
SCImago Journal Rank1.214
H-Index130
eISSN1440-1746
pISSN0815-9319
DOI10.1111/j.1440-1746.2006.04398.x

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