Vascular Targets for the Treatment of Portal Hypertension

2019 ◽  
Vol 39 (04) ◽  
pp. 483-501 ◽  
Author(s):  
Ksenia Brusilovskaya ◽  
Philipp Königshofer ◽  
Philipp Schwabl ◽  
Thomas Reiberger
Keyword(s):  
Portal Hypertension ◽  
Vascular Remodeling ◽  
Portal Pressure ◽  
Experimental Studies ◽  
Stellate Cells ◽  
Farnesoid X Receptor ◽  
Vascular Endothelial ◽  
Hepatic Inflammation ◽  
Main Driver ◽  
Intrahepatic Vascular Resistance

AbstractPortal hypertension is the main driver for severe complications in patients with liver cirrhosis. With improved understanding of molecular pathways that promote hepatic vascular remodeling, vasoconstriction, and sinusoidal capillarization potential vascular targets for the treatment of portal hypertension have been identified. Inhibition of vascular endothelial and platelet-derived growth factors–driven angiogenesis has been shown to reduce portal pressure and decrease hepatic inflammation. Angiopoietin/Tie signaling represents additional promising vascular targets in liver disease. The eNOS-NO-sGC-cGMP pathway modulates sinusoidal vasoconstriction and capillarization. Nuclear farnesoid X receptor (FXR) agonists decrease intrahepatic vascular resistance by inhibition of fibrogenesis and sinusoidal remodeling. Statins ameliorate endothelial dysfunction, decrease portal pressure, and reduce fibrogenesis. Anticoagulation with low-molecular heparin or anti-Xa inhibitors improved portal hypertension by deactivation of hepatic stellate cells and potentially via reduction of sinusoidal microthrombosis. This review summarizes important vascular targets for treatment of portal hypertension that have shown promising results in experimental studies.

scholarly journals Therapeutic Potential of MicroRNA: A New Target to Treat Intrahepatic Portal Hypertension?

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Can-Jie Guo ◽  
Qin Pan ◽  
Hua Xiong ◽  
Yu-Qi Qiao ◽  
Zhao-Lian Bian ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Vascular Resistance ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Stellate Cells ◽  
Therapeutic Benefit ◽  
Therapeutic Modality ◽  
Novel Drug ◽  
Intrahepatic Vascular Resistance ◽  
Novel Drug Targets

Intrahepatic portal hypertension accounts for most of the morbidity and mortality encountered in patients with liver cirrhosis, due to increased portal inflow and intrahepatic vascular resistance. Most treatments have focused only on portal inflow or vascular resistance. However, miRNA multitarget regulation therapy may potentially intervene in these two processes for therapeutic benefit in cirrhosis and portal hypertension. This review presents an overview of the most recent knowledge of and future possibilities for the use of miRNA therapy. The benefits of this therapeutic modality—which is poorly applied in the clinical setting—are still uncertain. Increasing the knowledge and current understanding of the roles of miRNAs in the development of intrahepatic portal hypertension and hepatic stellate cells (HSCs) functions, as well as their potential as novel drug targets, is critical.

scholarly journals The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 60
Author(s):  
Philipp Schwabl ◽  
Eva Hambruch ◽  
Grant R. Budas ◽  
Paul Supper ◽  
Michael Burnet ◽  
...  
Keyword(s):  
Blood Flow ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Target Genes ◽  
Portal Pressure ◽  
Farnesoid X Receptor ◽  
Systemic Hemodynamics ◽  
Splanchnic Blood Flow ◽  
Hydroxyproline Content ◽  
Sirius Red

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.

scholarly journals Endothelial cell-related autophagic pathways in Sugen/hypoxia-exposed pulmonary arterial hypertensive rats

2017 ◽  
Vol 313 (5) ◽  
pp. L899-L915 ◽  
Author(s):  
Fumiaki Kato ◽  
Seiichiro Sakao ◽  
Takao Takeuchi ◽  
Toshio Suzuki ◽  
Rintaro Nishimura ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Endothelial Cell ◽  
Vascular Remodeling ◽  
Time Dependent ◽  
Causative Role ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by progressive obstructive remodeling of pulmonary arteries. However, no reports have described the causative role of the autophagic pathway in pulmonary vascular endothelial cell (EC) alterations associated with PAH. This study investigated the time-dependent role of the autophagic pathway in pulmonary vascular ECs and pulmonary vascular EC kinesis in a severe PAH rat model (Sugen/hypoxia rat) and evaluated whether timely induction of the autophagic pathway by rapamycin improves PAH. Hemodynamic and histological examinations as well as flow cytometry of pulmonary vascular EC-related autophagic pathways and pulmonary vascular EC kinetics in lung cell suspensions were performed. The time-dependent and therapeutic effects of rapamycin on the autophagic pathway were also assessed. Sugen/hypoxia rats treated with the vascular endothelial growth factor receptor blocker SU5416 showed increased right ventricular systolic pressure (RVSP) and numbers of obstructive vessels due to increased pulmonary vascular remodeling. The expression of the autophagic marker LC3 in ECs also changed in a time-dependent manner, in parallel with proliferation and apoptotic markers as assessed by flow cytometry. These results suggest the presence of cross talk between pulmonary vascular remodeling and the autophagic pathway, especially in small vascular lesions. Moreover, treatment of Sugen/hypoxia rats with rapamycin after SU5416 injection activated the autophagic pathway and improved the balance between cell proliferation and apoptosis in pulmonary vascular ECs to reduce RVSP and pulmonary vascular remodeling. These results suggested that the autophagic pathway can suppress PAH progression and that rapamycin-dependent activation of the autophagic pathway could ameliorate PAH.

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.

Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension

2021 ◽  
Author(s):  
Nikolaj Rittig ◽  
Niels Kristian Aagaard ◽  
Gerda Elisabeth Villadsen ◽  
Thomas Damgaard Sandahl ◽  
Niels Jessen ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Clinical Study ◽  
Portal Pressure ◽  
Acute Effects

Telmisartan relieves liver fibrosis and portal hypertension by improving vascular remodeling and sinusoidal dysfunction

2021 ◽  
pp. 174713
Author(s):  
Lei Zheng ◽  
Zhifeng Zhao ◽  
Jiayun Lin ◽  
Hongjie Li ◽  
Guangbo Wu ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Vascular Remodeling

MAPK p38/Ulk1 pathway inhibits autophagy and induces IL-1β expression in hepatic stellate cells

2022 ◽  
Author(s):  
Li Jin ◽  
Juan Li ◽  
ShuJuan Yang ◽  
Rou Zhang ◽  
Chunhua Hu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Hepatic Inflammation ◽  
The Past ◽  
Cytokine Induction ◽  
Cytokines And Chemokines ◽  
The Relationship ◽  
Autophagy Inhibition ◽  
Lps Treatment

Background: In the past, hepatic stellate cells (HSCs) were considered to be noninflammatory cells and contribute to liver fibrosis by producing extracellular matrix. Recently, it was found that HSCs can also secrete cytokines and chemokines and therefore participate in hepatic inflammation. Autophagy participates in many immune response processes in immune cells. It is unclear whether autophagy is involved in inflammatory cytokine induction in HSCs. Methods: MAPK p38, Ulk1 phosphorylation and the Ulk1-Atg13 complex were analyzed in HSC-T6 cells after LPS treatment. The relationship between autophagy inhibition and inflammation was investigated in primary rat HSCs. Results: We discovered that LPS inhibited autophagy through MAPK p38. The activation of MAPK p38 induced Ulk1 phosphorylation, which disrupted the Ulk1-Atg13 complex and therefore inhibited autophagy. Furthermore, in primary rat HSCs, we demonstrated that autophagy inhibition regulated IL-1β induction, which depended on the MAPK p38/Ulk1 pathway. Conclusions: Our results reveal a continuous signaling pathway, MAPK p38-Ulk1 phosphorylation-Ulk1/Atg13 disruption, which inhibits autophagy and induces IL-1β expression in HSCs.

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