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Sodium Ferulate Reduces Portal Pressure Through Inhibition of RhoA/Rho-Kinase and Activation of Endothelial Nitric Oxide Synthase in Cirrhotic Rats.

Digestive diseases and sciences (2015-03-01)
Jiqiao Liu, Liping Peng, Juan Yang, Min Wang, Shengnan Xu, Jingmei Liu, Ping Han, Jiayi He, Dean Tian, Qi Zhou
ABSTRACT

Recent studies have demonstrated that increased RhoA/Rho-kinase activity and reduced nitric oxide activity have the necessary machinery to induce cirrhosis. However, it is unclear whether this regulates the functions of hepatic stellate cells (HSCs). In this study, we used sodium ferulate (SF) in a cirrhotic rat model and examined its roles in regulating RhoA activation in HSCs and the subsequent effects on contraction of HSCs. Bile duct ligation method was used to induce cirrhosis in rats. Intrahepatic resistance was investigated in in situ perfused livers. Hepatic RhoA, Rho-kinase and eNOS expressions were studied by RT-PCR and Western blot. RhoA pull-down assay and collagen gel contraction assay of HSCs were performed by incubation with SF in the absence or presence of GGPP. We showed that in cirrhotic liver, SF can efficiently affect RhoA activation via lowering the synthesis of GGPP in HSCs. These actions effectively reduced basal intrahepatic resistance in cirrhotic rats. Our study further suggested that SF effectively decreased Rho-kinase activity and increased activity of eNOS at both the mRNA and protein levels. SF treatment of HSCs reduced RhoA GTP without affecting the total RhoA protein level, and GGPP had the ability to block SF-induced protein expression. Furthermore, SF inhibited the contraction of activated HSCs and this inhibition was efficiently reversed by addition of GGPP. SF inhibits hepatic RhoA/Rho-kinase signaling and activates the NO/PKG pathway in cirrhotic rats. This may serve as a mechanism for reducing the contraction of activated HSCs upon SF treatment.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Acetic acid, natural, ≥99.5%, FG
Sigma-Aldrich
Bicinchoninic acid disodium salt hydrate, ≥98% (HPLC)
Sigma-Aldrich
Acetic acid, ≥99.5%, FCC, FG
Sigma-Aldrich
5α-Androstan-17β-ol-3-one, ≥97.5%
Sigma-Aldrich
Acetic acid, for luminescence, BioUltra, ≥99.5% (GC)
Sigma-Aldrich
Acetic acid-12C2, 99.9 atom % 12C