title: Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis.
abstract: Accumulating evidence indicates that hedgehog signaling plays a pivotal role in pathological angiogenesis and is involved in wound-healing responses in a number of adult tissues, including the liver. We previously demonstrated that hedgehog signaling promoted proliferation and inhibited apoptosis in hepatic stellate cells. This study was aimed to evaluate the effect of tetramethylpyrazine (TMP) on hedgehog signaling and to further examine the molecular mechanisms of TMP-induced antiangiogenesic effects in liver fibrosis. We found that TMP ameliorated the expression of proangiogenic markers vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGF-R2), platelet-derived growth factor BB (PDGF-BB), platelet-derived growth factor-β receptor (PDGF-βR) and hypoxia inducible factor 1α (HIF-1α), concomitant with reduced abundance of endothelial markers platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), CD34 and von willebrand factor in vivo and in vitro. Interestingly, TMP attenuated the abundance of sonic hedgehog, smoothened (Smo) and glioblastoma but increased the expression of hedgehog-interacting protein in liver sinusoidal endothelial cells, which was underlying mechanism for the antiangiogenesic activity of TMP. Downregulation of Smo activity, using selective Smo inhibitor cyclopamine, lead to a synergistic effect with TMP, whereas Smo overexpression plasmid impaired the induction of antiangiogenesic effects of TMP. Overall, these results provide novel implications to reveal the molecular mechanism of TMP-inhibited liver sinusoidal angiogenesis, by which points to the possibility of using TMP-based antiangiogenic drugs for the treatment of liver fibrosis. © 2017 IUBMB Life, 69(2):115-127, 2017.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
authors.forename: Jiangjuan
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, USA.
authors.forename: Anping
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009569:Nitric Oxide / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000235:genetics; D061251:Primary Cell Culture; D011719:Pyrazines / Q000008:administration & dosage*; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D053823:Hedgehog Proteins; D011719:Pyrazines; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D009569:Nitric Oxide; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase; C017953:tetramethylpyrazine
keywords: angiogenesis; hedgehog; liver fibrosis; liver sinusoidal endothelial cells; tetramethylpyrazine