Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo

Hepatology

Volumn 59, Issue 4, 2014, Pages 1492-1504

  Fallowfield, Jonathan A ^a   Hayden, Annette L ^b   Snowdon, Victoria K ^a   Aucott, Rebecca L ^a   Stutchfield, Ben M ^c   Mole, Damian J ^a   Pellicoro, Antonella ^a   Gordon Walker, Timothy T ^a   Henke, Alexander ^d   Schrader, Joerg ^a   Trivedi, Palak J ^e   Princivalle, Marc ^f   Forbes, Stuart J ^c   Collins, Jane E ^b   Iredale, John P ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

^b UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

^d UNIVERSITY OF EDINBURGH   (United Kingdom)

^e UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^f Ferring Research Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; ALPHA SMOOTH MUSCLE ACTIN; ANTIFIBROTIC AGENT; CARBON TETRACHLORIDE; CYTOSKELETON PROTEIN; GLIAL FIBRILLARY ACIDIC PROTEIN; HORMONE RECEPTOR; INDOCYANINE GREEN; MESSENGER RNA; NITRIC OXIDE; RECOMBINANT HORMONE; RECOMBINANT HUMAN GENE 2 RELAXIN; RELAXIN RECEPTOR 1; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; BILE DUCT LIGATION; BOLD SIGNAL; CAMP ASSAY; CARBON TETRACHLORIDE INTOXICATION; CELL ACTIVATION; CELL COUNT; CELL FUNCTION; CELL ISOLATION; CGMP ASSAY; CONFOCAL MICROSCOPY; CONNECTIVE TISSUE CELL; DOWN REGULATION; DRUG ACTIVATION; DRUG ACTIVITY; EMBRYO; FUNCTIONAL MAGNETIC RESONANCE IMAGING; GENE EXPRESSION; HEPATIC MYOFIBROBLAST; HEPATOBILIARY SYSTEM INFLAMMATION; HISTOPATHOLOGY; HORMONE BLOOD LEVEL; HUMAN; HUMAN CELL; IMMUNOASSAY; IMMUNOHISTOCHEMISTRY; IN VIVO STUDY; INTOXICATION; LIMIT OF QUANTITATION; LIVER CELL DAMAGE; LIVER CIRRHOSIS; LIVER FIBROSIS; LIVER FUNCTION; MALE; MEAN ARTERIAL PRESSURE; NITRIC OXIDE ANALYZER; NONHUMAN; OUTCOME ASSESSMENT; OXYGENATION; PORTAL HYPERTENSION; PORTAL VEIN BLOOD FLOW; PORTAL VEIN BLOOD PRESSURE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; QUANTITATIVE ANALYSIS; RAT; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; SMOOTH MUSCLE CONTRACTION; STELLATE CELL; TISSUE OXYGENATION; WESTERN BLOTTING;

ACTINS; ANIMALS; CARBON TETRACHLORIDE; CELLS, CULTURED; DESMIN; DISEASE MODELS, ANIMAL; GLIAL FIBRILLARY ACIDIC PROTEIN; HEMODYNAMICS; HUMANS; HYPERTENSION, PORTAL; LIVER; LIVER CIRRHOSIS; MALE; MYOFIBROBLASTS; NITRIC OXIDE; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, PEPTIDE; RELAXIN;

EID: 84896493187     PISSN: 02709139     EISSN: 15273350     Source Type: Journal    
DOI: 10.1002/hep.26627     Document Type: Article

References (34)

1. Reynaert H, Thompson MG, Thomas T, Geerts A. Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut 2000;50:571-581.
2. Thimgan MS, Yee HF Jr. Quantitation of rat hepatic stellate cell contraction: stellate cells' contribution to sinusoidal resistance. Am J Physiol 1999;277:137-143.
3. De Franchis R. Stellate cells and the "reversible component" of portal hypertension. Dig Liv Dis 2000;32:104-107.
4. Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325-337.
5. Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998;114:344-351.
6. Perri RE, Langer DA, Chatterjee S, Gibbons SJ, Gadgil J, Cao S, et al. Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation. Am J Physiol Gastrointest Liver Physiol 2006;290:G535-G542.
7. Carrión JA, Navasa M, García-Retortillo M, García-Pagan JC, Crespo G, Bruguera M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007;132:1746-1756.
8. Cardoso JE, Giroux L, Kassissia I, Houssin D, Habib N, Huet PM, et al. Liver function improvement following increased portal blood flow in cirrhotic rats. Gastroenterology 1994;107:460-467.
9. Sherwood OD. Relaxin's physiological roles and other diverse actions. Endocrine Rev 2004;25:205-234.
10. Hsu SY. New insights into the evolution of the relaxin-LGR signaling system. Trends Endocrinol Metab 2003;14:303-309.
11. Halls ML. Constitutive formation of an RXFP1-signalosome: a novel paradigm in GPCR function and regulation. Br J Pharmacol 2012;165:1644-1658.
12. Williams EJ, Benyon RC, Trim N, Hadwin R, Grove BH, Arthur MJ, et al. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut 2001;49:577-583.
13. Moller S, Emmeluth C, Henriksen JH. Elevated circulating plasma endothelin-1 concentrations in cirrhosis. J Hepatol 1993;19:285-290.
14. Kawada N, Tran-Thi TA, Klein H, Decker K. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem 1993;213:815-823.
15. Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent vasodilator in conscious rats. J Clin Invest 1999;103:525-533.
16. Danielson LA, Kercher LJ, Conrad KP. Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Physiol Regul Integr Comp Physiol 2000;279:1298-1304.
17. Ramachandran P, Pellicoro A, Vernon M, Boulter L, Aucott RL, Ali A, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 2012;109:E3186-E195.
18. Foley LM, Picot P, Thompson RT, Yau MJ, Brauer M. In vivo monitoring of hepatic oxygenation changes in chronically ethanol-treated rats by functional magnetic resonance imaging. Magn Reson Med 2003;50:976-983.
19. Gaca MD, Zhou X, Issa R, Kiriella K, Iredale JP, Benyon RC. Basement membrane-like matrix inhibits proliferation and collagen synthesis by activated rat hepatic stellate cells: evidence for matrix-dependent deactivation of stellate cells. Matrix Biol 2003;22:229-239.
20. Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002;36:200-209.
21. Debra DO, Conrad KP, Danielson LA, Shroff SG. Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response. J Appl Physiol 2005;98:1013-1020.
22. Kawaguchi Y, Ishizawa T, Miyata Y, Yamashita S, Masuda K, Satou S, et al. Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green. J Hepatol 2013;58:247-253.
23. Abraldes JG, Pasarín M, García-Pagán JC. Animal models of portal hypertension. World J Gastroenterol 2006;12:6577-6584.
24. Conrad KP. Renal hemodynamics during pregnancy in chronically catheterized, conscious rats. Kidney Int 1984;26:24-29.
25. Kisseleva T, Cong M, Paik Y, Scholten D, Jiang C, Benner C, et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A 2012;109:9448-9453.
26. Heeg MHJ, Koziolek MJ, Vasko R, Schaefer L, Sharma K, Muller GA, et al. The antifibrotic effects of relaxin in human renal myofibroblasts are mediated in part by inhibition of the Smad2 pathway. Kidney Int 2005;68:96-109.
27. Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 1999;117:1222-1228.
28. Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernandez M, Garcia-Pagan JC, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004;126:749-755.
29. Salmerón JM, Ruiz del Arbol L, Ginès A, García-Pagán JC, Ginès P, Feu F, et al. Renal effects of acute isosorbide-5-mononitrate administration in cirrhosis. Hepatology 1993;17:800-806.
30. McGuane JT, Debrah JE, Sautina L. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology 2011;52:2786-2796.
31. Debrah DO, Conrad KP, Jeyabalan A, Danielson LA, Shroff SG. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats. Hypertension 2005;46:745-750.
32. Dschietzig T, Teichman S, Unemori E, Wood S, Boehmer J, Richter C, et al. Intravenous recombinant hunman relaxin in compensated heart failure: a safety, tolerability, and pharmacodynamic trial. J Cardiac Fail 2009;15:182-190.
33. Kawada N, Kuroki T, Kobayashi K, Inoue M, Kaneda K. Inhibition of myofibroblastic transformation of cultured rat hepatic stellate cells by methylxanthines and dibutyryl cAMP. Dig Dis Sci 1996;41:1022-1029.
34. Kawada N, Kuroki T, Uoya M, Inoue M, Kobayashi K. Smooth muscle alpha-actin expression in rat hepatic stellate cell is regulated by nitric oxide and cGMP production. Biochem Biophys Res Commun 1996;4;229:238-242.