Carvedilol attenuates carbon tetrachloride-induced liver fibrosis and hepatic sinusoidal capillarization in mice

Abstract

Aim

To investigate the effect of carvedilol on liver fibrosis and hepatic sinusoidal capillarization in mice with carbon tetrachloride (CCl₄)-induced fibrosis.

Methods

A liver fibrosis mouse model was induced by intraperitoneal CCl₄ injection for 8 weeks. The mice were divided into five experimental groups: the normal group, the oil group, the CCl₄ group, the CCl₄+carvedilol (5 mg/kg/d) group, and the CCl₄+carvedilol (10 mg/kg/d) group. The extent of liver fibrosis was evaluated by histopathological staining, and the changes in fenestrations of hepatic sinus endothelial cells were observed by scanning electron microscope (SEM). The expression of α-smooth muscle actin (α-SMA) and vascular endothelial markers was detected by immunohistochemistry and Western blot assays. The effect of carvedilol on cell apoptosis was studied via Terminal deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL) assay, and the serum levels of matrix metalloproteinase-8 (MMP-8), vascular endothelial growth factor (VEGF), and angiopoietin-2 were detected through a Luminex assay.

Results

Liver fibrosis in CCl₄-treated mice was attenuated by reduced accumulation of collagen and the reaction of inflammation with carvedilol treatment. Carvedilol reduced the activation of hepatic stellate cells (HSCs) and increased the number of apoptotic cells. The expression of α-SMA, CD31, CD34 and VWF (von Willebrand factor) was significantly decreased after carvedilol treatment. In addition, the number of fenestrae in the hepatic sinusoid showed notable differences between the groups, and the serum levels of MMP-8, VEGF and angiopoietin-2 were increased in the mice with liver fibrosis and reduced by carvedilol treatment.

Conclusion

The study demonstrated that carvedilol could prevent further development of liver fibrosis and hepatic sinusoidal capillarization in mice with CCl₄-induced fibrosis.

Keywords:

• carvedilol
• liver fibrosis
• hepatic sinusoid
• angiogenesis
• hepatic stellate cell
• mice

Acknowledgment

The research was supported by National Natural Science Foundation of China, No. 81370590.

Disclosure

The authors report no conflicts of interest in this work.