title: Tetramethylpyrazine attenuates carbon tetrachloride-caused liver injury and fibrogenesis and reduces hepatic angiogenesis in rats.
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.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: Linnan
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: Qiuyi
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: Jiangjuan
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, PR China. Electronic address: nytws@163.com.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D002251:Carbon Tetrachloride / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D020574:Proto-Oncogene Proteins c-sis; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D000077214:Becaplermin; D002251:Carbon Tetrachloride; C000588866:KDR protein, human; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C017953:tetramethylpyrazine
keywords: Angiogenesis; Apoptosis; Capillarization; Liver fibrosis; Liver sinusoidal endothelial cell; Tetramethylpyrazine