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J Hepatol. 2012 Nov;57(5):967-73. doi: 10.1016/j.jhep.2012.07.012. Epub 2012 Jul 20.

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

Author information

1
Biochemistry and Molecular Genetics Service, Hospital Clínic Provincial de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.

Abstract

BACKGROUND & AIMS:

Platelet-derived growth factor (PDGF) is the most potent stimulus for proliferation and migration of stellate cells. PDGF receptor β (PDGFRβ) expression is an important phenotypic change in myofibroblastic cells that mediates proliferation and chemotaxis. Here we analyzed the relationship between PDGFRβ expression, hemodynamic deterioration, and fibrosis in CCl(4)-treated rats. Thereafter, we investigated the effects produced by an adenovirus encoding a dominant-negative soluble PDGFRβ (sPDGFRβ) on hemodynamic parameters, PDGFRβ signaling pathway, and fibrosis.

METHODS:

Mean arterial pressure, portal pressure, PDGFRβ 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 sPDGFRβ or β-galactosidase. After 7days, mean arterial pressure, portal pressure, serum sPDGFRβ, and hepatic collagen were measured.

RESULTS:

CCl(4)-treated animals for 18weeks showed a significantly higher increase in PDGFRβ mRNA compared to those treated for 13weeks and control rats. In CCl(4)-treated rats, the fibrous tissue area ranged from moderate to severe fibrosis. A direct relationship between the degree of fibrosis, hemodynamic changes, and PDGFRβ expression was observed. Fibrotic rats transduced with the adenovirus encoding sPDGFRβ showed increased mean arterial pressure, decreased portal pressure, lower activation of the PDGFRβ signaling pathway, and reduced hepatic collagen than fibrotic rats receiving β-galactosidase or saline.

CONCLUSIONS:

PDGFRβ activation closely correlates with hemodynamic disorders and increased fibrosis in CCl(4)-treated rats. Adenoviral dominant negative soluble PDGFRβ improved fibrosis. As a result, the hemodynamic abnormalities were ameliorated.

PMID:
22820479
DOI:
10.1016/j.jhep.2012.07.012
[Indexed for MEDLINE]

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