Tetramethylpyrazine attenuates carbon tetrachloride-caused liver injury and fibrogenesis and reduces hepatic angiogenesis in rats

• Published in: Biomedicine & pharmacotherapy 2017-02, Vol.86, p.521-530
• Main Authors: Zhao, Shifeng, Zhang, Zili, Qian, Linnan, Lin, Qiuyi, Zhang, Chenxi, Shao, Jiangjuan, Zhang, Feng, Zheng, Shizhong
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Capillarization; Carbon Tetrachloride - pharmacology; Down-Regulation - drug effects; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Internal Medicine; Liver - drug effects; Liver - metabolism; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver fibrosis; Liver sinusoidal endothelial cell; Male; Medical Education; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-sis - metabolism; Pyrazines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Platelet-Derived Growth Factor - metabolism; Tetramethylpyrazine; Up-Regulation - drug effects; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2016.11.122

Abstract Liver fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with abnormalities of angiogenesis in the liver. Capillarization of liver sinusoidal endothelial cell (LSEC) is the pivotal event during liver angiogenesis. In the current study, we sought to investigate the effect of tetramethylpyrazine (TMP) on carbon tetrachloride (CCl4 )-induced liver injury and fibrosis in rats, and to further examine the molecular mechanisms of TMP-induced anti-angiogenic effect. We found that TMP significantly ameliorated histopathological feature of liver fibrosis characterized by decreased collagen deposition, hepatocyte apoptosis, and expression of biochemical indicators, such as aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Moreover, TMP appeared to play an essential role in controlling pathological angiogenesis. In addition, TMP attenuated angiogenesis by downregulation of vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGF-R2), platelet-derived growth factor-BB (PDGF-BB), and platelet-derived growth factor-β receptor (PDGF-βR), four important factors transmitting pro-angiogenic pathways. Besides, TMP inhibited LSEC capillarization in CCl4 -induced liver fibrotic model with the morphological features of increasing sinusoidal fenestrae. Importantly, we found that disruption of angiogenesis is required for TMP to inhibit hepatocyte apoptosis in rats. Treatment with TMP significantly inhibited the expression of Bax, and up-regulated Bcl-2 expression. Interestingly, treatment with angiogenesis-inducer AngII dramatically eliminated the effect of TMP on Bax/Bcl-2 axis. Overall, these results provide novel perspectives to reveal the protective effect of TMP on liver, opening up the possibility of using TMP based anti-angiogenic drugs for the liver diseases.