Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 86, Issue -, Pages 521-530Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2016.11.122
Keywords
Liver fibrosis; Tetramethylpyrazine; Liver sinusoidal endothelial cell; Capillarization; Angiogenesis; Apoptosis
Funding
- National Natural Science Foundation of China [81270514, 31401210]
- Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica [JKLPSE 201502]
- Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Youth Natural Science Foundation of Jiangsu Province [BK20140955]
- Natural Science Research General Program of Jiangsu Higher Education Institutions [14KJB310011]
- Youth Natural Science Foundation of Nanjing University of Chinese Medicine [13XZR20]
- Priority Academic Pro-gram Development of Jiangsu Higher Education Institutions [ysxk-2010]
- Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education
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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-beta receptor (PDGF-beta R), 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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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