The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells

Hepatology ◽  
2017 ◽  
Vol 65 (6) ◽  
pp. 2031-2044 ◽  
Author(s):  
Marina Vilaseca ◽  
Héctor García-Calderó ◽  
Erica Lafoz ◽  
Oihane García-Irigoyen ◽  
Matías A. Avila ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells

2006 ◽  
Vol 291 (5) ◽  
pp. G877-G884 ◽  
Author(s):  
Pau Sancho-Bru ◽  
Ramón Bataller ◽  
Jordi Colmenero ◽  
Xavier Gasull ◽  
Montserrat Moreno ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Stellate Cells ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Cell Contraction

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through α1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-α1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-κB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed α1A-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed α1A-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (α1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific β-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-α1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-κB activation. BAY 11-7082, a specific NF-κB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-κB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.

scholarly journals Endothelin-1 in portal hypertension: The intricate role of hepatic stellate cells

2020 ◽  
Vol 245 (16) ◽  
pp. 1504-1512 ◽  
Author(s):  
Devaraj Ezhilarasan
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Chronic Liver ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells ◽  
Endothelin 1 ◽  
Activated Hepatic Stellate Cells

Portal hypertension is one of the most important cirrhosis-associated complications of chronic liver disease, leading to significant morbidity and mortality. After chronic liver injury, hepatic stellate cells reside in the perisinusoidal space activted and acquire a myofibroblast-like phenotype. The activated hepatic stellate cells act as both sources as well as the target for a potent vasoconstrictor endothelin-1. Activation of hepatic stellate cells plays a vital role in the onset of cirrhosis by way of increased extracellular matrix production and the enhanced contractile response to vasoactive mediators such as endothelin-1. In fibrotic/cirrhotic liver, activated hepatic stellate cells produce endothelin-1 leading to an imbalance between pro and antifibrotic factors responsible for enormous extracellular matrix synthesis. Thus, extracellular matrix deposition in the perisinusoidal space further augments liver stiffness and elevates the vascular tone and portal hypertension. Portal hypertension is a complex process modulated by several cell types like hepatic stellate cells, liver sinusoidal endothelial cells, Kupffer cells, injured hepatocytes, immune cells, and biliary epithelial cells. Therefore, targeting a single cell type may not be useful for regression of cirrhosis and portal hypertension. Nevertheless, numerous findings indicate that functionally liver sinusoidal endothelial cells and hepatic stellate cells closely regulate the sinusoidal blood flow via synthesis of several vasoactive molecules including endothelin-1, and hence targeting these cells with novel pharmacological agents may offer promising results. Impact statement Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.

Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats

2017 ◽  
Vol 37 (7) ◽  
pp. 1002-1012 ◽  
Author(s):  
Marina Vilaseca ◽  
Héctor García-Calderó ◽  
Erica Lafoz ◽  
Maria Ruart ◽  
Cristina Isabel López-Sanjurjo ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

scholarly journals Liver cirrhosis and hepatic stellate cells

2006 ◽  
Vol 21 (suppl 1) ◽  
pp. 54-57 ◽  
Author(s):  
Daniel Ferracioli Brandão ◽  
Leandra Naira Zambelli Ramalho ◽  
Fernando Silva Ramalho ◽  
Sérgio Zucoloto ◽  
Ana de Lourdes Candolo Martinelli ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Therapeutic Option ◽  
Stellate Cells ◽  
Terminal Phase ◽  
Activation Process ◽  
Bioactive Substances ◽  
Hepatic Diseases ◽  
Cytoplasmic Processes

The cirrhosis represents the final stage of several chronic hepatic diseases and it is characterized by the presence of fibrosis and morphologic conversion from the normal hepatic architecture into structurally abnormal nodules. In the evolution of the disease there is loss of the normal vascular relationship and portal hypertension. There are also regenerative hepatocelular alterations that become more prominent with the progression of the disease. The liver transplantation continues to be the only therapeutic option in cases of disease in terminal phase. The hepatic stellate cells (HSC) are perisinusoidal cells that store vitamin A and produce growth factors, citocins, prostaglandins and other bioactive substances. They can suffer an activation process that convert them to cells with a phenotype similar to myofibroblasts. When activated, they present increased capacity of proliferation, mobility, contractility and synthesis of collagen and other components of extracelular matrix. They possess cytoplasmic processes adhered to sinusoids and can affect the sinusoidal blood flow. HSC are important in pathogenesis of fibrosis and portal hypertension.

scholarly journals Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni

2015 ◽  
Vol 129 (10) ◽  
pp. 875-883 ◽  
Author(s):  
Thiago A. Pereira ◽  
Wing-Kin Syn ◽  
Mariana V. Machado ◽  
Paula V. Vidigal ◽  
Vivian Resende ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Schistosomiasis Mansoni

Schistosomal egg antigens induce host bile ductular cells to proliferate and produce osteopontin (OPN), a pro-fibrogenic factor that stimulates hepatic stellate cells to become myofibroblasts. The numbers of OPN-producing bile ductules correlate with fibrogenesis and portal hypertension in humans and mice.

Effects of nitric oxide (NO)-donors on activated human hepatic stellate cells (HSC): cellular basis for the treatment of portal hypertension

1998 ◽  
Vol 28 ◽  
pp. 46
Author(s):  
R.M.S. DeFranco ◽  
A. Caligiuri ◽  
P. Failli ◽  
A. Gentilini ◽  
R. Romanelli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
No Donors ◽  
Cellular Basis

Rivaroxaban Reduces Portal Hypertension in Cirrhotic Rats by Deactivating Hepatic Stellate Cells and Reducing Intrahepatic Microthrombosis

2016 ◽  
Vol 64 (2) ◽  
pp. S710-S711 ◽  
Author(s):  
M. Vilaseca ◽  
C.I. López-Sanjurjo ◽  
E. Lafoz ◽  
H. García-Calderó ◽  
O. García-Irigoyen ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

scholarly journals Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension

2016 ◽  
Vol 64 (4) ◽  
pp. 823-833 ◽  
Author(s):  
Rajiv Jalan ◽  
Francesco De Chiara ◽  
Vairappan Balasubramaniyan ◽  
Fausto Andreola ◽  
Varun Khetan ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Pathological Changes
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