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

• Published in: Journal of hepatology 2012-11, Vol.57 (5), p.967-973
• Main Authors: Reichenbach, V, Fernández-Varo, G, Casals, G, Oró, D, Ros, J, Melgar-Lesmes, P, Weiskirchen, R, Morales-Ruiz, M, Jiménez, W
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Ad-sPDGFRβ adenoviruses; Adenoviridae - genetics; Animals; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Biological and medical sciences; Carbon Tetrachloride - adverse effects; Collagen - metabolism; Disease Models, Animal; Disease Progression; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hemodynamics - physiology; Hepatic collagen; In Vitro Techniques; Liver - blood supply; Liver - metabolism; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - physiopathology; Male; Medical sciences; PDGFRβ; Portal pressure; Portal Pressure - physiology; Rats; Rats, Wistar; Receptor, Platelet-Derived Growth Factor beta - genetics; Receptor, Platelet-Derived Growth Factor beta - metabolism; Signal Transduction - physiology; Signaling pathway blockade; Systemic hemodynamics; Transduction, Genetic
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2012.07.012

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 CCl4 -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 7 days, mean arterial pressure, portal pressure, serum sPDGFRβ, and hepatic collagen were measured. Results CCl4 -treated animals for 18 weeks showed a significantly higher increase in PDGFRβ 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 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 CCl4 -treated rats. Adenoviral dominant negative soluble PDGFRβ improved fibrosis. As a result, the hemodynamic abnormalities were ameliorated.