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1
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Wang Y, Liu X, Quan X, Qin X, Zhou Y, Liu Z, Chao Z, Jia C, Qin H, Zhang H. Pigment epithelium-derived factor and its role in microvascular-related diseases. Biochimie 2022; 200:153-171. [DOI: 10.1016/j.biochi.2022.05.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 05/19/2022] [Accepted: 05/30/2022] [Indexed: 01/02/2023]
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2
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XSSJS inhibits hepatic fibrosis by promoting the mir29b-3p/VEGFA axis in vitro and in vivo. Biosci Rep 2022; 42:230729. [PMID: 35118493 PMCID: PMC8881647 DOI: 10.1042/bsr20212241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 01/21/2022] [Accepted: 02/02/2022] [Indexed: 11/22/2022] Open
Abstract
Hepatic pathological angiogenesis (HPA) is the key event of hepatic fibrosis (HF). Xueshisanjia powder (XSSJS), a Chinese herbal compound, is beneficial for alleviating pathological angiogenesis of hepatic tissue. The present study attempts to reveal the effect and mechanism of XSSJS via regulating miR-29b-3p/VEGFA axis against pathological angiogenesis in HF. In in vitro model, human embryonic kidney 293T cells were transfected with miR-29b-3p mimics, whereby the expression of miR-29b-3p was tested by real-time quantitative polymerase chain reaction (RT-qPCR), ensued by Luciferase assay determining the relationship between miR-29b-3p and vascular endothelial cell growth factor A (VEGFA). In addition, miR-29b-3p mimic transfected into the activated hepatic stellate cell T6 (HSC-T6). The Cell-Counting-Kit 8 (CCK8) and 5-Bromodeoxyuridine (BrdU) staining were first utilized to detect the antiproliferative efficiency of XSSJS following the XSSJS compound serum intervention, and then used to observe the expression of transforming growth factor-β (TGF-β), VEGFA, platelet-derived growth factor (PDGF) via RT-PCR, Western blot (WB), and Immunofluorescence (IF) methods. During the in vivo model, XSSJS with boil-free granules were fed to Wistar rats with liver fibrosis caused by intraperitoneal injection of pig serum followed by the transfection of miR-29b-3p adeno-associated virus (AAV). Hematoxylin–Eosin (HE) staining was used for histopathology assessment. The expression of miR-29b-3p, VEGFA, PDGF, TGF-β have been investigated in liver tissue using RT-PCR, WB, IF. The results verified that XSSJS could up-regulate miR-29b-3p and suppress the expression of VEGFA, PDGA, and TGF-β. In mechanism, miR-29b-3p primarily targeted the 3′UTR of VEGFA. In conclusion, XSSJS could modulate miR-29b-3p/VEGFA axis to inhibit the pathological angiogenesis of HF.
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3
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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4
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Uschner FE, Schueller F, Nikolova I, Klein S, Schierwagen R, Magdaleno F, Gröschl S, Loosen S, Ritz T, Roderburg C, Vucur M, Kristiansen G, Lammers T, Luedde T, Trebicka J. The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension. Oncotarget 2018; 9:36220-36237. [PMID: 30546838 PMCID: PMC6281422 DOI: 10.18632/oncotarget.26333] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 10/24/2018] [Indexed: 02/06/2023] Open
Abstract
Background and Aims Angiogenesis is critically involved in the development of liver fibrosis, portal hypertension (PHT) and hepatocellular carcinoma (HCC). Regorafenib is a novel second-line therapy for HCC, but might also be beneficial in fibrosis and PHT even in absence of HCC. This study investigated the effects of regorafenib in experimental models without HCC. Methods Fibrosis (in vivo and in vitro), inflammation, liver damage (aminotransferases), angiogenesis (matrigel implantation) and in vivo systemic and portal hemodynamics were assessed in different mouse and rat models (bile duct ligation, CCl4, partial portal vein ligation) after acute and chronic treatment with regorafenib. Results Long-term treatment with regorafenib improved portal hypertension most likely due to blunted angiogenesis, without affecting fibrosis progression or regression. Interestingly, acute administration of regorafenib also ameliorated portal hemodynamics. Although regorafenib treatment led to hepatotoxic side effects in long-term treated fibrotic animals, in partial portal vein ligated rats, no liver toxicity due to regorafenib was observed. Discussion Regorafenib might be especially suitable as therapy in patients with PHT and preserved liver function.
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Affiliation(s)
- Frank Erhard Uschner
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.,Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - Florian Schueller
- Department of Internal Medicine III, University of Aachen, Aachen, Germany
| | - Ivelina Nikolova
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Sabine Klein
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.,Institute of Cellular Medicine, Fibrosis Research Group, Newcastle upon Tyne, United Kingdom.,Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | | | | | - Stefanie Gröschl
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Sven Loosen
- Department of Internal Medicine III, University of Aachen, Aachen, Germany
| | - Thomas Ritz
- Department of Internal Medicine III, University of Aachen, Aachen, Germany
| | | | - Michael Vucur
- Department of Internal Medicine III, University of Aachen, Aachen, Germany
| | | | - Twan Lammers
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, University of Aachen, Aachen, Germany
| | - Tom Luedde
- Department of Internal Medicine III, University of Aachen, Aachen, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.,Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.,Institute for Bioengineering of Catalonia, Barcelona, Spain.,Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
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5
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Kostallari E, Hirsova P, Prasnicka A, Verma VK, Yaqoob U, Wongjarupong N, Roberts LR, Shah VH. Hepatic stellate cell-derived platelet-derived growth factor receptor-alpha-enriched extracellular vesicles promote liver fibrosis in mice through SHP2. Hepatology 2018; 68:333-348. [PMID: 29360139 PMCID: PMC6033667 DOI: 10.1002/hep.29803] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 01/17/2018] [Accepted: 01/18/2018] [Indexed: 12/11/2022]
Abstract
UNLABELLED Liver fibrosis is characterized by the activation and migration of hepatic stellate cells (HSCs), followed by matrix deposition. Recently, several studies have shown the importance of extracellular vesicles (EVs) derived from liver cells, such as hepatocytes and endothelial cells, in liver pathobiology. While most of the studies describe how liver cells modulate HSC behavior, an important gap exists in the understanding of HSC-derived signals and more specifically HSC-derived EVs in liver fibrosis. Here, we investigated the molecules released through HSC-derived EVs, the mechanism of their release, and the role of these EVs in fibrosis. Mass spectrometric analysis showed that platelet-derived growth factor (PDGF) receptor-alpha (PDGFRα) was enriched in EVs derived from PDGF-BB-treated HSCs. Moreover, patients with liver fibrosis had increased PDGFRα levels in serum EVs compared to healthy individuals. Mechanistically, in vitro tyrosine720-to-phenylalanine mutation on the PDGFRα sequence abolished enrichment of PDGFRα in EVs and redirected the receptor toward degradation. Congruently, the inhibition of Src homology 2 domain tyrosine phosphatase 2, the regulatory binding partner of phosphorylated tyrosine720, also inhibited PDGFRα enrichment in EVs. EVs derived from PDGFRα-overexpressing cells promoted in vitro HSC migration and in vivo liver fibrosis. Finally, administration of Src homology 2 domain tyrosine phosphatase 2inhibitor, SHP099, to carbon tetrachloride-administered mice inhibited PDGFRα enrichment in serum EVs and reduced liver fibrosis. CONCLUSION PDGFRα is enriched in EVs derived from PDGF-BB-treated HSCs in an Src homology 2 domain tyrosine phosphatase 2-dependent manner and these PDGFRα-enriched EVs participate in development of liver fibrosis. (Hepatology 2018;68:333-348).
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Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Alena Prasnicka
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN,Department of Pharmacology, Charles University, Hradec Kralove, Czech Republic
| | - Vikas K. Verma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Usman Yaqoob
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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Therapeutic siRNA targeting endothelial KDR decreases portosystemic collateralization in portal hypertension. Sci Rep 2017; 7:14791. [PMID: 29093528 PMCID: PMC5665956 DOI: 10.1038/s41598-017-14818-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/13/2017] [Indexed: 02/08/2023] Open
Abstract
Development of portosystemic collateral vessels and gastroesophageal varices is responsible for the most serious clinical consequences of portal hypertension, but effective clinical therapies are limited. Here we developed and investigated the therapeutic potential of an innovative liposomally-formulated short-interfering RNA (siRNA) technology based on clinical stage components, capable to attenuate production of the endothelial kinase insert domain receptor (KDR), which controls portosystemic collateralization and contributes to disease progression and aggravation. These siRNAs were first validated in vitro, and then, their therapeutic potential on portosystemic collateralization and pathological angiogenesis was tested in vivo in mouse models of portal hypertension (portal vein-ligation). siRNAKDR-lipoplexes efficiently transported siRNAKDR to vascular endothelial cells in mesenteric microvenules and portal vein of portal hypertensive mice, where collaterogenesis and angiogenesis take place. This systemic treatment significantly downregulated pathological KDR overexpression, without causing complete KDR knockout, preserving homeostatic baseline KDR levels and thus limiting adverse effects. siRNAKDR-lipoplex-induced endothelial-specific KDR knockdown drastically reduced by 73% the portosystemic collateralization, and impaired the pathologic angiogenic potential of vascular endothelial cells at different levels (cell proliferation, sprouting and remodeling). Targeting endothelial KDR with therapeutic siRNAKDR-lipoplexes could be a promising and plausible treatment modality for attenuating the formation of portosystemic collaterals in a clinical setting.
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Xuan J, Chen Y, Zhu L, Guo Y, Deng L, Zheng Y, Wang Z, Wang Z, Ao M. Ultrasound molecular imaging with cRGD-PLGA-PFOB nanoparticles for liver fibrosis staging in a rat model. Oncotarget 2017; 8:108676-108691. [PMID: 29312560 PMCID: PMC5752473 DOI: 10.18632/oncotarget.21358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 08/28/2017] [Indexed: 12/15/2022] Open
Abstract
Hepatic fibrosis is the only chronic liver disease process that can be reversed. Developing non-invasive and effective methods to quantitatively assess the degree of liver fibrosis is of great clinical significance and remains a major challenge. The key factors in hepatic fibrosis pathogenesis are the activation and proliferation of hepatic stellate cells that subsequently express integrin αvβ3. An ultrasound (US) agent combined with a targeting peptide may be used for the early and non-invasive diagnosis of hepatic fibrosis. Herein, we report the synthesis of core-shell nanoparticles (NPs) successfully engineered by conjugation with cyclic arginine-glycine-aspartic acid (cRGD) octapeptide, allowing hepatic integrin αvβ3 targeting for liver fibrosis staging. This system consists of a perfluorooctyl bromide (PFOB) liquid in the core that is stabilized with a Poly (lactic-co-glycolic acid) (PLGA) polymer shell and modified with a cRGD. These core-shell NPs (cRGD-PLGA-PFOB NPs) exhibited useful US molecular imaging features including high imaging contrast among liver fibrotic stages and the adjacent tissues. Our results indicate that the cRGD-PLGA-PFOB NPs have significant potential to distinguish different liver fibrotic stages and could be used in clinical applications.
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Affiliation(s)
- Jiqing Xuan
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China.,Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yuli Chen
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China
| | - Leilei Zhu
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China
| | - Yuan Guo
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China
| | - Liming Deng
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China
| | - Yuanyi Zheng
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China.,Institute of Ultrasound in Medicine, Shanghai Jiaotong University Affiliated Shanghai Sixth People's Hospital, Shanghai 200233, China
| | - Zhaoxia Wang
- Department of Ultrasound, The Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhigang Wang
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China
| | - Meng Ao
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China
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8
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Raoul JL, Gilabert M, Adhoute X, Edeline J. An in-depth review of chemical angiogenesis inhibitors for treating hepatocellular carcinoma. Expert Opin Pharmacother 2017; 18:1467-1476. [PMID: 28893090 DOI: 10.1080/14656566.2017.1378346] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a frequent and severe complication of cirrhosis. Most HCC patients initially present with or progress to advanced stage disease and require systemic treatment. As hypervascularization is a major characteristic of HCC, antiangiogenic drugs have been tested. Areas covered: In this review, we summarize data on the use of drugs targeting the angiogenesis. Despite many trials, in 2017 only 3 drugs, all antiangiogenic, have demonstrated efficacy in first (sorafenib, lenvatinib) or second line (regorafenib) treatment of advanced HCC. The heterogeneous mechanisms of action and the major reasons for failure of most trials are discussed. An English-language, abstract-based literature review was performed by a PubMed-based strategy. Expert opinion: Currently all trials based on purely antiangiogenic compounds (bevacizumab, linifanib, brivanib and ramucirumab) or drugs with strong antiangiogenic properties (sunitinib) have failed (increased toxicity, minor efficacy and/or flaws in trial design); sorafenib, lenvatinib and regorafenib are multityrosine kinase inhibitors and their efficacy can be partly related to another mechanism of action. We need to better refine future trials design (randomized phase 2, good stratification factors and marker-enriched patient selection) in order to progress toward customized treatment, perhaps in association with immunotherapy.
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Affiliation(s)
- Jean-Luc Raoul
- a Department of Medical Oncology , Paoli-Calmettes Institute , Marseille , France
| | - Marine Gilabert
- a Department of Medical Oncology , Paoli-Calmettes Institute , Marseille , France
| | - Xavier Adhoute
- b Department of Hepato-Gastroenterology , Hôpital Saint-Joseph , Marseille , France
| | - Julien Edeline
- c Department of Medical Oncology , Center Eugène Marquis , Rennes , France
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9
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Garcia-Pras E, Gallego J, Coch L, Mejias M, Fernandez-Miranda G, Pardal R, Bosch J, Mendez R, Fernandez M. Role and therapeutic potential of vascular stem/progenitor cells in pathological neovascularisation during chronic portal hypertension. Gut 2017; 66:1306-1320. [PMID: 26984852 DOI: 10.1136/gutjnl-2015-311157] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/09/2016] [Accepted: 02/24/2016] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Pathological neovascularisation is intimately involved in portal hypertension (PH). Here, we determined the contribution of vascular stem/progenitor cells (VSPCs) to neovessel growth in PH and whether the RNA-binding protein cytoplasmic polyadenylation element binding protein-4 (CPEB4) was behind the mechanism controlling VSPC function. DESIGN To identify and monitor VSPCs in PH rats (portal vein-ligated), we used a combinatorial approach, including sphere-forming assay, assessment of self-renewal, 5-bromo-2'-desoxyuridine label retention technique, in vitro and in vivo stem/progenitor cell (SPC) differentiation and vasculogenic capability, cell sorting, as well as immunohistochemistry, immunofluorescence and confocal microscopy expression analysis. We also determined the role of CPEB4 on VSPC proliferation using genetically engineered mouse models. RESULTS We demonstrated the existence in the mesenteric vascular bed of VSPCs displaying capability to form cellular spheres in suspension culture, self-renewal ability, expression of molecules commonly found in SPCs, slow-cycling features, in addition to other cardinal properties exhibited by SPCs, like capacity to differentiate into endothelial cells and pericytes with remarkable vasculogenic activity. Such VSPCs showed, after PH induction, an early switch in proliferation, and differentiated in vivo into endothelial cells and pericytes, contributing, structurally and functionally, to abnormal neovessel formation. Quantification of VSPC-dependent neovessel formation in PH further illustrated the key role played by VSPCs. We also demonstrated that CPEB4 regulates the proliferation of the activated VSPC progeny upon PH induction. CONCLUSIONS These findings demonstrate that VSPC-derived neovessel growth (ie, vasculogenesis) and angiogenesis cooperatively stimulate mesenteric neovascularisation in PH and identify VSPC and CPEB4 as potential therapeutic targets.
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Affiliation(s)
- Ester Garcia-Pras
- IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Javier Gallego
- IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Laura Coch
- IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Marc Mejias
- IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Gonzalo Fernandez-Miranda
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ricardo Pardal
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Jaime Bosch
- IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Raul Mendez
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Mercedes Fernandez
- IDIBAPS Biomedical Research Institute, CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
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10
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Abstract
In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.
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Affiliation(s)
- Juan Cristóbal Gana
- Department of Pediatric Gastroenterology & Nutrition, Division of Pediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile. Chile
| | - Carolina A Serrano
- Department of Pediatric Gastroenterology & Nutrition, Division of Pediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile. Chile
| | - Simon C Ling
- Division of Gastroenterology, Hepatology & Nutrition, Department of Paediatrics, University of Toronto, and The Hospital for Sick Children, Toronto, Canada
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11
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Fratta LXS, Hoss GRW, Longo L, Uribe-Cruz C, da Silveira TR, Vieira SMG, Kieling CO, dos Santos JL. Hypoxic-ischemic gene expression profile in the isolated variant of biliary atresia. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:846-854. [DOI: 10.1002/jhbp.297] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Leila Xavier Sinigaglia Fratta
- Experimental Laboratory of Hepatology and Gastroenterology; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
| | - Giovana Regina Weber Hoss
- Experimental Laboratory of Hepatology and Gastroenterology; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
| | - Larisse Longo
- Experimental Laboratory of Hepatology and Gastroenterology; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
| | - Carolina Uribe-Cruz
- Experimental Laboratory of Hepatology and Gastroenterology; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
| | - Themis Reverbel da Silveira
- Experimental Laboratory of Hepatology and Gastroenterology; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
| | - Sandra Maria Gonçalves Vieira
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
- Pediatric Hepatology Unit; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
| | - Carlos Oscar Kieling
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
- Pediatric Hepatology Unit; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
| | - Jorge Luiz dos Santos
- Experimental Laboratory of Hepatology and Gastroenterology; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
- Graduate Program in Gastroenterology and Hepatology; Universidade Federal do Rio Grande do Sul; Porto Alegre Brazil
- Pediatric Hepatology Unit; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
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12
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Bocca C, Novo E, Miglietta A, Parola M. Angiogenesis and Fibrogenesis in Chronic Liver Diseases. Cell Mol Gastroenterol Hepatol 2015; 1:477-488. [PMID: 28210697 PMCID: PMC5301407 DOI: 10.1016/j.jcmgh.2015.06.011] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 06/02/2015] [Indexed: 12/12/2022]
Abstract
Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles.
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Key Words
- ANGPTL3, angiopoietin-like-3 peptide
- Akt, protein kinase B
- Ang-1, angiopoietin-1
- CCL2, chemokine ligand 2
- CCR, chemokine receptor
- CLD, chronic liver disease
- ET-1, endothelin 1
- HCC, hepatocellular carcinoma
- HIF, hypoxia-inducible factor
- HSC, hepatic stellate cell
- HSC/MFs, myofibroblast-like cells from activated hepatic stellate cells
- Hh, Hedgehog
- Hypoxia
- LSEC, liver sinusoidal endothelial cell
- Liver Angiogenesis
- Liver Fibrogenesis
- MF, myofibroblast
- MP, microparticle
- Myofibroblasts
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NO, nitric oxide
- PDGF, platelet-derived growth factor
- ROS, reactive oxygen species
- VEGF, vascular endothelial growth factor
- VEGF-R2, vascular endothelial growth factor receptor type 2
- eNOS, endothelial nitric oxide synthase
- α-SMA, α-smooth muscle actin
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Affiliation(s)
| | | | | | - Maurizio Parola
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, School of Medicine, University of Torino, Torino, Italy
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Ding Q, Tian XG, Li Y, Wang QZ, Zhang CQ. Carvedilol may attenuate liver cirrhosis by inhibiting angiogenesis through the VEGF-Src-ERK signaling pathway. World J Gastroenterol 2015; 21:9566-76. [PMID: 26327764 PMCID: PMC4548117 DOI: 10.3748/wjg.v21.i32.9566] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/15/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of carvedilol on angiogenesis and the underlying signaling pathways. METHODS The effect of carvedilol on angiogenesis was examined using a human umbilical vascular endothelial cell (HUVEC) model. The effect of carvedilol on cell viability was measured by CCK8 assay. Flow cytometry was used to assess the effect of carvedilol on cell cycle progression. Cell migration, transwell migration and tube formation assays were performed to analyze the effect of carvedilol on HUVEC function. Vascular endothelial growth factor (VEGF) induced activation of HUVECs, which were pretreated with different carvedilol concentrations or none. Western blot analysis detected the phosphorylation levels of three cell signaling pathway proteins, VEGFR-2, Src, and extracellular signal-regulated kinase (ERK). The specific Src inhibitor PP2 was used to assess the role of Src in the VEGF-induced angiogenic pathway. RESULTS Carvedilol inhibited HUVEC proliferation in a dose-dependent manner (IC50 = 38.5 mmol/L). The distribution of cells in the S phase decreased from 43.6% to 37.2%, 35.6% and 17.8% by 1, 5 and 10 μmol/L carvedilol for 24 h, respectively. Carvedilol (10 μmol/L) reduced VEGF-induced HUVEC migration from 67.54 ± 7.83 to 37.11 ± 3.533 (P < 0.001). Carvedilol concentrations of 5 μmol/L and 10 μmol/L reduced cell invasion from 196.3% ± 18.76% to 114.0% ± 12.20% and 51.68% ± 8.28%, respectively. VEGF-induced tube formation was also reduced significantly by 5 μmol/L and 10 μmol/L carvedilol from 286.0 ± 36.72 to 135.7 ± 18.13 (P < 0.05) and 80.27 ± 11.16 (P < 0.01) respectively. We investigated several intracellular protein levels to determine the reason for these reductions. Treatment with 10 μmol/L carvedilol reduced VEGF-induced tyrosine phosphorylation of VEGFR-2 from 175.5% ± 8.54% to 52.67% ± 5.33% (P < 0.01). Additionally, 10 μmol/L carvedilol reduced VEGF-induced ERK 1/2 phosphorylation from 181.9% ± 18.61% to 56.45% ± 7.64% (P < 0.01). The VEGF-induced increase in Src kinase activity was alleviated by carvedilol [decreased from 141.8% ± 15.37% to 53.57 ± 7.18% (P < 0.01) and 47.04% ± 9.74% (P < 0.01) at concentrations of 5 and 10 μmol/L, respectively]. Pretreatment of HUVECs with Src kinase inhibitor almost completely prevented the VEGF-induced ERK upregulation [decreased from 213.2% ± 27.68% to 90.96% ± 17.16% (P < 0.01)]. CONCLUSION Carvedilol has an anti-angiogenic effect on HUVECs. This inhibitory effect is mediated by VEGF-induced Src-ERK signaling pathways.
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Fernandez M. Molecular pathophysiology of portal hypertension. Hepatology 2015; 61:1406-15. [PMID: 25092403 DOI: 10.1002/hep.27343] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 07/27/2014] [Indexed: 12/11/2022]
Abstract
Over the past two decades the advances in molecular cell biology have led to significant discoveries about the pathophysiology of portal hypertension (PHT). In particular, great progress has been made in the study of the molecular and cellular mechanisms that regulate the increased intrahepatic vascular resistance (IHVR) in cirrhosis. We now know that the increased IHVR is not irreversible, but that both the structural component caused by fibrosis and the active component caused by hepatic sinusoidal constriction can be, at least partially, reversed. Indeed, it is now apparent that the activation of perisinusoidal hepatic stellate cells, which is a key event mediating the augmented IHVR, is regulated by multiple signal transduction pathways that could be potential therapeutic targets for PHT treatment. Furthermore, the complexity of the molecular physiology of PHT can also be appreciated when one considers the complex signals capable of inducing vasodilatation and hyporesponsiveness to vasoconstrictors in the splanchnic vascular bed, with several vasoactive molecules, controlled at multiple levels, working together to mediate these circulatory abnormalities. Added to the complexity is the occurrence of pathological angiogenesis during the course of disease progression, with recent emphasis given to understanding its molecular machinery and regulation. Although much remains to be learned, with the current availability of reagents and new technologies and the exchange of concepts and data among investigators, our knowledge of the molecular basis of PHT will doubtless continue to grow, accelerating the transfer of knowledge generated by basic research to clinical practice. This will hopefully permit a better future for patients with PHT.
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Affiliation(s)
- Mercedes Fernandez
- Angiogenesis in Liver Disease Research Group, Institute of Biomedical Research IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
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15
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Mejias M, Coch L, Berzigotti A, Garcia-Pras E, Gallego J, Bosch J, Fernandez M. Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats. Gut 2015; 64:657-66. [PMID: 24848263 DOI: 10.1136/gutjnl-2014-307138] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Antiangiogenic strategies have been proposed as a promising new approach for the therapy of portal hypertension and chronic liver disease. Pigment epithelium-derived factor (PEDF) is a powerful endogenous angiogenesis inhibitor whose role in portal hypertension remains unknown. Therefore, we aimed at determining the involvement of PEDF in cirrhotic portal hypertension and the therapeutic efficacy of its supplementation. DESIGN PEDF expression profiling and its relationship with vascular endothelial growth factor (VEGF), neovascularisation and fibrogenesis was determined in bile duct-ligated (BDL) rats and human cirrhotic livers. The ability of exogenous PEDF overexpression by adenovirus-mediated gene transfer (AdPEDF) to inhibit angiogenesis, fibrogenesis and portal pressure was also evaluated in BDL rats, following prevention and intervention trials. RESULTS PEDF was upregulated in cirrhotic human and BDL rat livers. PEDF and VEGF protein expression and localisation in mesentery and liver increased in parallel with portal hypertension progression, being closely linked in time and space with mesenteric neovascularisation and liver fibrogenesis in BDL rats. Furthermore, AdPEDF increased PEDF bioavailability in BDL rats, shifting the net balance in the local abundance of positive (VEGF) and negative (PEDF) angiogenesis drivers in favour of attenuation of portal hypertension-associated pathological neovascularisation. The antiangiogenic effects of AdPEDF targeted only pathological angiogenesis, without affecting normal vasculature, and were observed during early stages of disease. AdPEDF also significantly decreased liver fibrogenesis (through metalloproteinase upregulation), portosystemic collateralisation and portal pressure in BDL rats. CONCLUSIONS This study provides compelling experimental evidence indicating that PEDF could be a novel therapeutic agent worthy of assessment in portal hypertension and cirrhosis.
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Affiliation(s)
- Marc Mejias
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Laura Coch
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Annalisa Berzigotti
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Ester Garcia-Pras
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Javier Gallego
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Jaime Bosch
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Mercedes Fernandez
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
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Abstract
Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases (CLDs) that are characterized by inflammation and progressive fibrosis. Because anti-angiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical and experimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis.
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Affiliation(s)
- Gülsüm Özlem Elpek
- Gülsüm Özlem Elpek, Department of Pathology, Akdeniz University Medical School, 07070 Antalya, Turkey
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Coch L, Mejias M, Berzigotti A, Garcia-Pras E, Gallego J, Bosch J, Mendez R, Fernandez M. Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats. Hepatology 2014; 60:633-47. [PMID: 24390792 DOI: 10.1002/hep.26995] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 12/28/2013] [Indexed: 12/21/2022]
Abstract
UNLABELLED Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis. CONCLUSION Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis.
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Affiliation(s)
- Laura Coch
- Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain
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18
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Fan TT, Hu PF, Wang J, Wei J, Zhang Q, Ning BF, Yin C, Zhang X, Xie WF, Chen YX, Shi B. Regression effect of hepatocyte nuclear factor 4α on liver cirrhosis in rats. J Dig Dis 2013; 14:318-27. [PMID: 23374293 DOI: 10.1111/1751-2980.12042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to determine whether cirrhosis could be reversed after treated with hepatocyte nuclear factor 4α (HNF4α), a key transcriptional regulator of hepatocyte differentiation and function. METHODS Early and advanced stages of liver cirrhosis were induced by thioacetamide (TAA) administration. The adenovirus carrying HNF4α gene was injected into cirrhotic rats via the tail vein. The effect of HNF4α on cirrhosis was evaluated by histological and immunohistochemical examination. RESULTS Early stage of cirrhosis was remarkably resolved by HNF4α to a nearly-normal extent and advanced cirrhosis was partially ameliorated in vivo. The enforced expression of HNF4α downregulated profibrogenic factors remarkably including α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, fibroblast-specific protein (FSP)-1, collagen I and III. In vivo and in vitro studies revealed that HNF4α administration inhibited extracellular signal-regulated kinase (ERK) signaling pathway through the downregulation of phosphorated ERK and phosphorated JunD. In addition, HNF4α readjusted the balance between extracellular matrix deposition and degradation through the upregulation of matrix metalloproteinase and downregulation of its inhibitors. Moreover, HNF4α treatment inhibited angiogenesis as determined by CD31 and CD34 immunostaining. CONCLUSIONS Our findings broaden the knowledge on the reversibility of different stages of cirrhosis as HNF4α could present a promising alternative for the treatment of liver cirrhosis.
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Affiliation(s)
- Ting Ting Fan
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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Sahin H, Borkham-Kamphorst E, Kuppe C, Zaldivar MM, Grouls C, Al-samman M, Nellen A, Schmitz P, Heinrichs D, Berres ML, Doleschel D, Scholten D, Weiskirchen R, Moeller MJ, Kiessling F, Trautwein C, Wasmuth HE. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 2012; 55:1610-9. [PMID: 22237831 DOI: 10.1002/hep.25545] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Recent data suggest that the chemokine receptor CXCR3 is functionally involved in fibroproliferative disorders, including liver fibrosis. Neoangiogenesis is an important pathophysiological feature of liver scarring, but a functional role of angiostatic CXCR3 chemokines in this process is unclear. We therefore investigated neoangiogenesis in carbon tetrachloride (CCl(4))-induced liver fibrosis in Cxcr3(-/-) and wildtype mice by histological, molecular, and functional imaging methods. Furthermore, we assessed the direct role of vascular endothelial growth factor (VEGF) overexpression on liver angiogenesis and the fibroproliferative response using a Tet-inducible bitransgenic mouse model. The feasibility of attenuation of angiogenesis and associated liver fibrosis by therapeutic treatment with the angiostatic chemokine Cxcl9 was systematically analyzed in vitro and in vivo. The results demonstrate that fibrosis progression in Cxcr3(-/-) mice was strongly linked to enhanced neoangiogenesis and VEGF/VEGFR2 expression compared with wildtype littermates. Systemic VEGF overexpression led to a fibrogenic response within the liver and was associated with a significantly increased Cxcl9 expression. In vitro, Cxcl9 displayed strong antiproliferative and antimigratory effects on VEGF-stimulated endothelial cells and stellate cells by way of reduced VEGFR2 (KDR), phospholipase Cγ (PLCγ), and extracellular signal-regulated kinase (ERK) phosphorylation, identifying this chemokine as a direct counter-regulatory molecule of VEGF signaling within the liver. Accordingly, systemic administration of Cxcl9 led to a strong attenuation of neoangiogenesis and experimental liver fibrosis in vivo. CONCLUSION The results identify direct angiostatic and antifibrotic effects of the Cxcr3 ligand Cxcl9 in a model of experimental liver fibrosis. The amelioration of liver damage by systemic application of Cxcl9 might offer a novel therapeutic approach for chronic liver diseases associated with increased neoangiogenesis.
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Affiliation(s)
- Hacer Sahin
- Medical Department III, University Hospital Aachen, Aachen, Germany
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20
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Liu Y, Wang Z, Kwong SQ, Lui ELH, Friedman SL, Li FR, Lam RWC, Zhang GC, Zhang H, Ye T. Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib. J Hepatol 2011; 55:612-625. [PMID: 21251937 DOI: 10.1016/j.jhep.2010.11.035] [Citation(s) in RCA: 143] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2010] [Revised: 10/31/2010] [Accepted: 11/25/2010] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Nilotinib is a novel tyrosine kinase inhibitor of Bcr-Abl and other kinases. In this study, we have examined its activity as an anti-fibrotic agent. METHODS The in vitro effect of Nilotinib on rat and human HSCs was assessed using proliferation assays and Western blotting. The in vivo antifibrotic efficacy of Nilotinib was assessed in mice with liver fibrosis induced by CCl(4) and bile duct ligation (BDL). RESULTS Nilotinib inhibited proliferation, migration, and actin filament formation, as well as the expression of α-SMA and collagen in activated HSCs. Nilotinib induced apoptosis of HSCs, which was correlated with reduced bcl-2 expression, increased p53 expression, cleavage of PARP, as well as increased expression of PPARγ and TRAIL-R. Nilotinib also induced cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibited activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibited PDGF and TGFβ-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFβ-activated phosphorylated form(s) of Abl in human HSCs were inhibited by Nilotinib. In vivo, Nilotinib reduced collagen deposition and α-SMA expression in CCl(4) and BDL-induced fibrosis. These beneficial effects were associated with suppressed expression of procollagen-(I), TIMP-1, CD31, CD34, VEGF, and VEGFR. Nilotinib could induce HSC undergoing apoptosis in vivo, which was correlated with downregulation of bcl-2. We also observed reduced expression of phosphorylated ERK, Akt, and Abl in the Nilotinib-treated CCl(4) and BDL livers. In addition to its antifibrotic activity, the drug was hepatoprotective and reduced the elevations of ALT and AST after CCl(4) and BDL. CONCLUSIONS These studies uncover a novel role of Bcr-Abl activity in treatment of liver fibrosis through multiple mechanisms and indicate that Nilotinib represents a potentially effective antifibrotic agent.
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Affiliation(s)
- Yuqing Liu
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen 518055, China.
| | - Zhuo Wang
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Shu Qin Kwong
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Eric Lik Hang Lui
- Department of Biochemistry, The University of Hong Kong, Hong Kong, China
| | - Scott L Friedman
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA
| | - Fu Rong Li
- Clinical Medical Research Center, The Second Clinic Medicine College, Shenzhen People's Hospital, Jinan University, Shenzhen 518020, China
| | - Reni Wing Chi Lam
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Guo Chao Zhang
- Clinical Medical Research Center, The Second Clinic Medicine College, Shenzhen People's Hospital, Jinan University, Shenzhen 518020, China
| | - Hui Zhang
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen 518055, China
| | - Tao Ye
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, The Shenzhen Graduate School of Peking University, Shenzhen 518055, China.
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Coriat R, Gouya H, Mir O, Ropert S, Vignaux O, Chaussade S, Sogni P, Pol S, Blanchet B, Legmann P, Goldwasser F. Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib. PLoS One 2011; 6:e16978. [PMID: 21340026 PMCID: PMC3038868 DOI: 10.1371/journal.pone.0016978] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Accepted: 01/15/2011] [Indexed: 12/12/2022] Open
Abstract
Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients.
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Affiliation(s)
- Romain Coriat
- Center for Research on Angiogenesis Inhibitors (CERIA), Hôpital Cochin, AP-HP, Paris, France.
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22
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Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol 2010; 53:976-80. [PMID: 20800926 DOI: 10.1016/j.jhep.2010.07.004] [Citation(s) in RCA: 217] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Revised: 07/07/2010] [Accepted: 07/12/2010] [Indexed: 02/06/2023]
Abstract
Portal hypertension accounts for the majority of morbidity and mortality that is encountered in patients with cirrhosis. Portal hypertension is initiated in large part through increases in intrahepatic vascular resistance. Fibrosis, regenerative nodule formation, and intrahepatic vasoconstriction are classical mechanisms that account for increased intrahepatic vascular resistance in cirrhosis. Recent data suggest that intrahepatic angiogenesis and sinusoidal remodeling could also be involved in sinusoidal resistance, fibrosis, and portal hypertension. While angiogenesis is defined as the formation of new vessels deriving from existing ones, sinusoidal remodeling in its pathological form associated with cirrhosis is characterized by increased mural coverage of vessels by contractile HSC. Most attention on the mechanisms of these processes has focused on the liver sinusoidal endothelial cell (SEC), the hepatic stellate cell (HSC), and the paracrine signaling pathways between these two cell types. Interventions that target these vascular structural changes have beneficial effects on portal hypertension and fibrosis in some animal studies which has stimulated interest for pursuing parallel studies in humans with portal hypertension.
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Affiliation(s)
- Dominique Thabut
- Gastroenterology Research Unit, Advanced Liver Disease Study Group, Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN, USA
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23
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Lee JW. [Treatment update on portal hypertension and complications]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2010; 56:144-54. [PMID: 20847605 DOI: 10.4166/kjg.2010.56.3.144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Current understanding of the pathophysiology of portal hypertension has resulted in therapeutic approaches aimed at correcting the increased splanchnic blood flow and some of which have been already used in clinical practice. Recently new perspectives opened and erstwhile paradigm has been changed to focus on increased resistance to portal blood flow and the formation of portosystemic collateralization. Several studies revealed the clear-cut mechanisms of hepatic endothelial dysfunction and abnormal angiogenesis contributing to the development of portal hypertension. Thus the modulations of hyperdynamic circulation or angiogenesis seem to be valuable therapeutic targets. In the current review update, we discuss the multidisciplinary management of modulating hepatic vascular resistance and abnormal angiogenesis associated with portal hypertension. However, these new pharmacological approaches are still under investigation and widescale clinical application are needed to develop effective strategies.
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Affiliation(s)
- Jin Woo Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.
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Bosch J, Abraldes JG, Fernández M, García-Pagán JC. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol 2010; 53:558-67. [PMID: 20561700 DOI: 10.1016/j.jhep.2010.03.021] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Revised: 03/19/2010] [Accepted: 03/19/2010] [Indexed: 12/12/2022]
Abstract
Portal hypertension is the main cause of complications in patients with chronic liver disease. Over the past 25 years, progress in the understanding of the pathophysiology of portal hypertension was followed by the introduction of an effective pharmacological therapy, consisting mainly of treatments aimed at correcting the increased splanchnic blood flow. It is only recently that this paradigm has been changed. Progress in our knowledge of the mechanisms of increased resistance to portal blood flow, of the formation of portal-systemic collaterals, and of mechanisms other than vasodilatation maintaining the increased splanchnic blood flow have opened entirely new perspectives for developing more effective treatment strategies. This is the aim of the current review, which focuses on: (a) the modulation of hepatic vascular resistance by correcting the increased hepatic vascular tone due to hepatic endothelial dysfunction, and (b) correcting the abnormal angiogenesis associated with portal hypertension, which contributes to liver inflammation and fibrogenesis, to the hyperkinetic splanchnic circulation, and to the formation of portal-systemic collaterals and varices.
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Affiliation(s)
- Jaume Bosch
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain.
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Paternostro C, David E, Novo E, Parola M. Hypoxia, angiogenesis and liver fibrogenesis in the progression of chronic liver diseases. World J Gastroenterol 2010; 16:281-8. [PMID: 20082471 PMCID: PMC2807946 DOI: 10.3748/wjg.v16.i3.281] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis is a dynamic, hypoxia-stimulated and growth factor-dependent process, and is currently referred to as the formation of new vessels from pre-existing blood vessels. Experimental and clinical studies have unequivocally reported that hepatic angiogenesis, irrespective of aetiology, occurs in conditions of chronic liver diseases (CLDs) characterized by perpetuation of cell injury and death, inflammatory response and progressive fibrogenesis. Angiogenesis and related changes in liver vascular architecture, that in turn concur to increase vascular resistance and portal hypertension and to decrease parenchymal perfusion, have been proposed to favour fibrogenic progression of the disease towards the end-point of cirrhosis. Moreover, hepatic angiogenesis has also been proposed to modulate the genesis of portal-systemic shunts and increase splanchnic blood flow, thus potentially affecting complications of cirrhosis. Hepatic angiogenesis is also crucial for the growth and progression of hepatocellular carcinoma. Recent literature has identified a number of cellular and molecular mechanisms governing the cross-talk between angiogenesis and fibrogenesis, with a specific emphasis on the crucial role of hypoxic conditions and hepatic stellate cells, particularly when activated to the myofibroblast-like pro-fibrogenic phenotype. Experimental anti-angiogenic therapy has been proven to be effective in limiting the progression of CLDs in animal models. From a clinical point of view, anti-angiogenic therapy is currently emerging as a new pharmacologic intervention in patients with advanced fibrosis and cirrhosis.
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