Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl₄-induced cirrhotic rats

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, p-vasodilator-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.

Keywords

portal hypertension / cirrhosis / urotensin II / palosuran / hepatic stellate cell

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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).

Compliance with ethics guidelines

Ruoxi Zhang, Jing Chen, Diangang Liu, and Yu Wang declare that they have no conflicts of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

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