Abstract
Increased serum urotensin II (UII) levels in human cirrhotic populations have been recently shown, but the long-term effects of UII receptor antagonist on the cirrhosis have not been investigated. To investigate the therapeutic effects of urotensin II receptor (UT) antagonist palosuran on rats with carbon tetrachloride (CCl4)-induced cirrhosis, the hepatic and systemic hemodynamics, liver fibrosis, the metalloproteinase-13 (MMP-13)/tissue inhibitor of metalloproteinase-1 (TIMP-1) ratio, hepatic Rho-kinase activity, and the endothelial nitric oxide synthase (eNOS) activity are measured in CCl4-cirrhotic rats treated with palosuran or vehicle for 4 weeks. Primary hepatic stellate cells (HSCs) are used to investigate the changes in UII/UT expression and the in vitro effect of palosuran. Compared with the vehicle-treated cirrhotic rats, treatment with palosuran can reduce the portal pressure (PP), decrease the risk of liver fibrosis and the level of α smooth muscle actin, collagen-I (COL-I), and transforming growth factor β expression. However, treatment with palosuran can increase MMP-13/TIMP-1, pvasodilator-stimulated phosphoprotein (p-VASP), and p-eNOS expression. Moreover, in vitro UII/UT mRNA expression increases during HSC activation. MMP-13/TIMP-1, COL-I, and p-VASP are inhibited after palosuran treatment. Our data indicate that long-term administration of palosuran can decrease PP in cirrhosis, which results from decreased hepatic fibrosis and enhanced eNOS-dependent HSC vasodilatation.
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Groszmann RJ, Abraldes JG. Portal hypertension: from bedside to bench. J Clin Gastroenterol 2005; 6(4 Suppl 2): S125–S130
McConnell M, Iwakiri Y. Biology of portal hypertension. Hepatol Int 2018; 12(Suppl 1):11–23
Vilaseca M, García-Calderó H, Lafoz E, García-Irigoyen O, Avila MA, Reverter JC, Bosch J, Hernández-Gea V, Gracia-Sancho J, García-Pagán JC. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017; 65(6): 2031–2044
Vilaseca M, García-Calderó H, Lafoz E, Ruart M, López-Sanjurjo CI, Murphy MP, Deulofeu R, Bosch J, Hernández-Gea V, Gracia-Sancho J, García-Pagán JC. Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats. Liver Int 2017; 37(7): 1002–1012
Rockey DC, Fouassier L, Chung JJ, Carayon A, Vallee P, Rey C, Housset C. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998; 27(2): 472–480
Iwakiri Y. Pathophysiology of portal hypertension. Clin Liver Dis 2014; 18(2): 281–291
Nishimura Y, Ito T, Hoe K, Saavedra JM. Chronic peripheral administration of the angiotensin II AT(1) receptor antagonist candesartan blocks brain AT(1) receptors. Brain Res 2000; 871(1): 29–38
Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD, Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Ohlstein EH, Bergsma DJ, Douglas SA. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999; 401(6750): 282–286
Ross B, McKendy K, Giaid A. Role of urotensin II in health and disease. Am J Physiol Regul Integr Comp Physiol 2010; 298(5): R1156–R1172
Thanassoulis G, Huyhn T, Giaid A. Urotensin II and cardiovascular diseases. Peptides 2004; 25(10): 1789–1794
Kemp W, Roberts S, Krum H. Increased circulating urotensin II in cirrhosis: potential implications in liver disease. Peptides 2008; 29 (5): 868–872
Liu D, Chen J, Wang J, Zhang Z, Ma X, Jia J, Wang Y. Increased expression of urotensin II and GPR14 in patients with cirrhosis and portal hypertension. Int J Mol Med 2010; 25(6): 845–851
Liu DG, Wang J, Zhang ZT, Wang Y. The urotension II antagonist SB-710411 arrests fibrosis in CCl4 cirrhotic rats. Mol Med Rep 2009; 2(6): 953–961
Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C, Müller C, Nayler O, Qiu C, Rey M, Scherz MW, Velker J, Weller T, Xi JF, Ziltener P. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)- ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther 2004; 311(1): 204–212
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(4): 657–666
Clozel M, Hess P, Qiu C, Ding SS, Rey M. The urotensin-II receptor antagonist palosuran improves pancreatic and renal function in diabetic rats. J Pharmacol Exp Ther 2006; 316(3): 1115–1121
Hsu SJ, Lee FY, Wang SS, Hsin IF, Lin TY, Huang HC, Chang CC, Chuang CL, Ho HL, Lin HC, Lee SD. Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats. Hepatology 2015; 61(5): 1672–1684
Delgado MG, Gracia-Sancho J, Marrone G, Rodríguez-Vilarrupla A, Deulofeu R, Abraldes JG, Bosch J, García-Pagán JC. Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 2013; 305(7): G496–G502
Darlington AS, Dippel DW, Ribbers GM, van Balen R, Passchier J, Busschbach JJ. A prospective study on coping strategies and quality of life in patients after stroke, assessing prognostic relationships and estimates of cost-effectiveness. J Rehabil Med 2009; 41(4): 237–241
Mülsch A, Oelze M, Klöss S, Mollnau H, Töpfer A, Smolenski A, Walter U, Stasch JP, Warnholtz A, Hink U, Meinertz T, Münzel T. Effects of in vivo nitroglycerin treatment on activity and expression of the guanylyl cyclase and cGMP-dependent protein kinase and their downstream target vasodilator-stimulated phosphoprotein in aorta. Circulation 2001; 103(17): 2188–2194
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3(6): 1101–1108
Ramm GA. Isolation and culture of rat hepatic stellate cells. J Gastroenterol Hepatol 1998; 13(8): 846–851
Rockey DC, Weisiger RA. Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology 1996; 24 (1): 233–240
Liu J, Gong H, Zhang ZT, Wang Y. Effect of angiotensin II and angiotensin II type 1 receptor antagonist on the proliferation, contraction and collagen synthesis in rat hepatic stellate cells. Chin Med J (Engl) 2008; 121(2): 161–165
Kemp W, Krum H, Colman J, Bailey M, Yandle T, Richards M, Roberts S. Urotensin II: a novel vasoactive mediator linked to chronic liver disease and portal hypertension. Liver Int 2007; 27(9): 1232–1239
Kemp W, Kompa A, Phrommintikul A, Herath C, Zhiyuan J, Angus P, McLean C, Roberts S, Krum H. Urotensin II modulates hepatic fibrosis and portal hemodynamic alterations in rats. Am J Physiol Gastrointest Liver Physiol 2009; 297(4): G762–G767
Sidharta PN, Rave K, Heinemann L, Chiossi E, Krähenbühl S, Dingemanse J. Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with type 2 diabetes mellitus. Br J Clin Pharmacol 2009; 68(4): 502–510
Trebicka J, Leifeld L, Hennenberg M, Biecker E, Eckhardt A, Fischer N, Pröbsting AS, Clemens C, Lammert F, Sauerbruch T, Heller J. Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology 2008; 47 (4): 1264–1276
Heller J, Schepke M, Neef M, Woitas R, Rabe C, Sauerbruch T. Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension. J Hepatol 2002; 37(6): 767–772
Leifeld L, Clemens C, Heller J, Trebicka J, Sauerbruch T, Spengler U. Expression of urotensin II and its receptor in human liver cirrhosis and fulminant hepatic failure. Dig Dis Sci 2010; 55(5): 1458–1464
Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R, Kaur G. Matrix metalloproteinases and cancer-roles in threat and therapy. Asian Pac J Cancer Prev 2014; 15(3): 1085–1091
Liu LM, Liang DY, Ye CG, Tu WJ, Zhu T. The UII/UT system mediates upregulation of proinflammatory cytokines through p38 MAPK and NF-kB pathways in LPS-stimulated Kupffer cells. PLoS One 2015; 10(3): e0121383
Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002; 35(2): 478–491
Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Elst IV, Windmolders P, Vanuytsel T, Nevens F, Laleman W. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59(6): 2286–2298
Mallat A, Lotersztajn S. Targeting cannabinoid receptors in hepatocellular carcinoma. Gut 2016; 65(10):1582–1583
Cheng K, Yang N, Mahato RI. TGF-ß1 gene silencing for treating liver fibrosis. Mol Pharm 2009; 6(3): 772–779
Chen RJ, Wu HH, Wang YJ. Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89 (10): 1727–1750
Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, Nevens F, Sauerbruch T, Heller J. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007; 46(1): 242–253
Acknowledgements
This study was supported by the National Natural Science Foundation of China (No. 81170408 to Diangang Liu), the Wang Baoen Liver Fibrosis Research Foundation of the China Hepatitis Prevention Foundation (No. 20120124 to Diangang Liu), and the China Postdoctoral Science Foundation (No. 2012M510094 to Diangang Liu).
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Zhang, R., Chen, J., Liu, D. et al. Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl4-induced cirrhotic rats. Front. Med. 13, 398–408 (2019). https://doi.org/10.1007/s11684-019-0689-5
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DOI: https://doi.org/10.1007/s11684-019-0689-5