title: Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.
abstract: Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.
authors.affiliation: Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.|Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Jin-Hang
authors.initials: JH
authors.lastname: Gao
authors.affiliation: Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.|Department of Human Anatomy, Academy of Preclinical and Forensic Medicine, West China Medicine College, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Shi-Lei
authors.initials: SL
authors.lastname: Wen
authors.affiliation: Department of Human Anatomy, Academy of Preclinical and Forensic Medicine, West China Medicine College, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Shi
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Yao-Yao
authors.initials: YY
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Huan
authors.initials: H
authors.lastname: Tong
authors.affiliation: Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Shi-Hang
authors.initials: SH
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Zhi-Yin
authors.initials: ZY
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Jin-Hui
authors.initials: JH
authors.lastname: Yang
authors.affiliation: Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy and Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Hui-Qi
authors.initials: HQ
authors.lastname: Xie
authors.affiliation: Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China. shcqcdmed@163.com.|Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. shcqcdmed@163.com.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Tang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000068579:Celecoxib / Q000008:administration & dosage*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D004357:Drug Synergism; D006975:Hypertension, Portal / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D015282:Octreotide / Q000008:administration & dosage*; D017082:Portal Pressure / Q000187:drug effects; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013853:Thioacetamide / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D013853:Thioacetamide; D000068579:Celecoxib; D015282:Octreotide
keywords: Angiogenesis; Celecoxib; Hepatic arterioportal fistulas; Liver cirrhosis; Octreotide; Portal hypertension