Adenoviral dominant-negative soluble PDGFR beta improves hepatic collagen, systemic hemodynamics, and portal pressure in fibrotic rats

TítolAdenoviral dominant-negative soluble PDGFR beta improves hepatic collagen, systemic hemodynamics, and portal pressure in fibrotic rats
Publication TypeJournal Article
Year of Publication2012
AuthorsReichenbach V, Fernandez-Varo G, Casals G, Oro D, Ros J, Melgar-Lesmes P, Weiskirchen R, Morales-Ruiz M, Jimenez W
JournalJournal of Hepatology
Volume57
Pagination967-973
Date Published2012
ISBN Number0168-8278
AbstractBackground & Aims: Platelet-derived growth factor (PDGF) is the most potent stimulus for proliferation and migration of stellate cells. PDGF receptor beta (PDGFR beta) expression is an important phenotypic change in myofibroblastic cells that mediates proliferation and chemotaxis. Here we analyzed the relationship between PDGFR beta expression, hemodynamic deterioration, and fibrosis in CCl4-treated rats. Thereafter, we investigated the effects produced by an adenovirus encoding a dominant-negative soluble PDGFR beta (sPDGFR beta) on hemodynamic parameters, PDGFR beta signaling pathway, and fibrosis. Methods: Mean arterial pressure, portal pressure, PDGFR beta mRNA expression, and hepatic collagen were assessed in 6 controls and 21 rats induced to hepatic fibrosis/cirrhosis. Next, 30 fibrotic rats were randomized into three groups receiving iv saline and an adenovirus encoding for sPDGFR beta or beta-galactosidase. After 7 days, mean arterial pressure, portal pressure, serum sPDGFR beta, and hepatic collagen were measured. Results: CCl4-treated animals for 18 weeks showed a significantly higher increase in PDGFR beta mRNA compared to those treated for 13 weeks and control rats. In CCl4-treated rats, the fibrous tissue area ranged from moderate to severe fibrosis. A direct relationship between the degree of fibrosis, hemodynamic changes, and PDGFR beta expression was observed. Fibrotic rats transduced with the adenovirus encoding sPDGFR beta showed increased mean arterial pressure, decreased portal pressure, lower activation of the PDGFR beta signaling pathway, and reduced hepatic collagen than fibrotic rats receiving beta-galactosidase or saline. Conclusions: PDGFR beta activation closely correlates with hemodynamic disorders and increased fibrosis in CCl4-treated rats. Adenoviral dominant negative soluble PDGFR beta improved fibrosis. As a result, the hemodynamic abnormalities were ameliorated. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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