Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo
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Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. / Fallowfield, Jonathan A; Hayden, Annette L; Snowdon, Victoria K; Aucott, Rebecca L; Stutchfield, Ben M; Mole, Damian J; Pellicoro, Antonella; Gordon-Walker, Timothy T; Henke, Alexander; Schrader, Joerg; Trivedi, Palak J; Princivalle, Marc; Forbes, Stuart J; Collins, Jane E; Iredale, John P.
In: HEPATOLOGY, Vol. 59, No. 4, 01.04.2014, p. 1492-1504.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo
AU - Fallowfield, Jonathan A
AU - Hayden, Annette L
AU - Snowdon, Victoria K
AU - Aucott, Rebecca L
AU - Stutchfield, Ben M
AU - Mole, Damian J
AU - Pellicoro, Antonella
AU - Gordon-Walker, Timothy T
AU - Henke, Alexander
AU - Schrader, Joerg
AU - Trivedi, Palak J
AU - Princivalle, Marc
AU - Forbes, Stuart J
AU - Collins, Jane E
AU - Iredale, John P
N1 - Copyright © 2014 by the American Association for the Study of Liver Diseases.
PY - 2014/4/1
Y1 - 2014/4/1
N2 - Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner. Conclusion: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status.
AB - Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner. Conclusion: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status.
KW - Actins
KW - Animals
KW - Carbon Tetrachloride
KW - Cells, Cultured
KW - Desmin
KW - Disease Models, Animal
KW - Glial Fibrillary Acidic Protein
KW - Hemodynamics
KW - Humans
KW - Hypertension, Portal
KW - Liver
KW - Liver Cirrhosis
KW - Male
KW - Myofibroblasts
KW - Nitric Oxide
KW - Rats
KW - Rats, Sprague-Dawley
KW - Receptors, G-Protein-Coupled
KW - Receptors, Peptide
KW - Relaxin
U2 - 10.1002/hep.26627
DO - 10.1002/hep.26627
M3 - SCORING: Journal article
C2 - 23873655
VL - 59
SP - 1492
EP - 1504
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 4
ER -
