Hepatic Overexpression of PDGF-B in Transgenic Mouse Model Leads to Cell Apoptosis

PDGF-B is the strongest mitogenic factor for mesenchymal cells. Transgenic mice with liver-specific overexpression of PDGF-B under controll of the murine albumin promoter have been shown to develop fibrotic lesions in the liver. Expression of the transgene in act-cre/PDGF-B double transgenic mice from early embryonic stages or tamoxifen-induced transgene expression in adult animals- ttr-cre/PDGF-B mice, results in proliferation/activation of hepatic stellate cells (HSC) and similar fibrotic phenotype of the liver differing only in severity grade. There are also data that show a proapoptotic effects of PDGF-B. We investigated the possible proapoptotic effects of PDGF-B in the PDGF-B transgenic mice. Histological comparison of HE-stained liver samples from double-transgenic mice with hepatic overexpression of PDGF-B and those of control animals shows pericentral areas of cell necrosis/apoptosis in transgenic mice. A significant raise in serum GLDH level (p<0.05) as marker for pericentral hepatocyte necrosis was found in double-transgenic mice in comparison to control animals. Also in TUNEL apoptosis-assay a significant increase of the number of apoptotic cells was found in PDGF-B overexpressing mice in comparison to controls. An increase of bcl-xs mRNA-an inductor of apoptosis was found in our model.. There is evidence for the pro-apoptotic effects of PDGF-B in vascular smooth muscle cells in vitro. In our model PDGF-B is shown to trigger liver-cell death in vivo. Bcl-xs mRNA induction sheds light on mechanism of the apoptosis.

Keywords: PDGF-B, fibrosis, liver, transgenic mice