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Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: a preliminary study.

Wei L, Yang J, Wang M, Xu SN, Liang HM, Zhou Q - Int. J. Mol. Med. (2014)

Bottom Line: Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage.Following the addition of GGPP, the rate apoptotic rate decreased.SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.

ABSTRACT
Cirrhotic rats show higher expression levels of hepatic RhoA and Rho-kinase than normal healthy rats, and the activation of this signaling pathway leads to portal hypertension. Sodium ferulate (SF) has been shown to decrease the production of geranylgeranyl pyrophosphate (GGPP), a substance essential for RhoA activation. In the present study, to investigate the effects of SF on fibrosis, portal hypertension and the RhoA/Rho-kinase pathway, hepatic cirrhosis was induced in rats by bile duct ligation. Liver function and fibrogenesis-related biochemical parameters, the hepatic hydroxyproline content, the pathological characteristics of the liver sections and the levels of hepatic α-smooth muscle actin (α-SMA; by immunohistochemistry) were analyzed to assess effects of SF on hepatic fibrosis. In addition, hepatic RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) expression was examined by immunohistochemistry. Apoptosis in the SF-treated and SF + GGPP-treated rat primary hepatic stellate cells (HSCs) and a human stellate cell line (LX-2) was examined by flow cytometry. Intrahepatic resistance and responsiveness to the α1-adrenoceptor agonist, methoxamine, were investigated by in situ liver perfusion. Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage. The SF-treated rats had a significantly lower expression of α-SMA and Rho-kinase, as well as an increased hepatic eNOS content; however, SF did not affect RhoA expression. The SF-treated HSCs had a significantly increased apoptotic rate compared to the untreated rats. Following the addition of GGPP, the rate apoptotic rate decreased. SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine. Therefore, our data demonstrate that SF reduces fibrogenesis, decreases portal pressure in cirrhotic rats and inhibits the activation of the RhoA/Rho-kinase signaling pathway.

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Related in: MedlinePlus

Representative immunohistochemical staining for control, α-smooth muscle actin (α-SMA), RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) staining in the 3 groups. Control, α-SMA, RhoA, Rho-kinase and eNOS immunohistochemical staining is shown for the sham-operated + normal saline (SHAM + NS), bile duct ligation + normal saline (BDL + NS) and bile duct ligation + sodium ferulate (BDL + SF) groups.
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f3-ijmm-34-05-1257: Representative immunohistochemical staining for control, α-smooth muscle actin (α-SMA), RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) staining in the 3 groups. Control, α-SMA, RhoA, Rho-kinase and eNOS immunohistochemical staining is shown for the sham-operated + normal saline (SHAM + NS), bile duct ligation + normal saline (BDL + NS) and bile duct ligation + sodium ferulate (BDL + SF) groups.

Mentions: The histological results for antibody staining for α-SMA, RhoA, Rho-kinase and eNOS in the hepatic cells are shown in Fig. 3, and the corresponding semi-quantitative data are shown in Fig. 4.


Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: a preliminary study.

Wei L, Yang J, Wang M, Xu SN, Liang HM, Zhou Q - Int. J. Mol. Med. (2014)

Representative immunohistochemical staining for control, α-smooth muscle actin (α-SMA), RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) staining in the 3 groups. Control, α-SMA, RhoA, Rho-kinase and eNOS immunohistochemical staining is shown for the sham-operated + normal saline (SHAM + NS), bile duct ligation + normal saline (BDL + NS) and bile duct ligation + sodium ferulate (BDL + SF) groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199412&req=5

f3-ijmm-34-05-1257: Representative immunohistochemical staining for control, α-smooth muscle actin (α-SMA), RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) staining in the 3 groups. Control, α-SMA, RhoA, Rho-kinase and eNOS immunohistochemical staining is shown for the sham-operated + normal saline (SHAM + NS), bile duct ligation + normal saline (BDL + NS) and bile duct ligation + sodium ferulate (BDL + SF) groups.
Mentions: The histological results for antibody staining for α-SMA, RhoA, Rho-kinase and eNOS in the hepatic cells are shown in Fig. 3, and the corresponding semi-quantitative data are shown in Fig. 4.

Bottom Line: Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage.Following the addition of GGPP, the rate apoptotic rate decreased.SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.

ABSTRACT
Cirrhotic rats show higher expression levels of hepatic RhoA and Rho-kinase than normal healthy rats, and the activation of this signaling pathway leads to portal hypertension. Sodium ferulate (SF) has been shown to decrease the production of geranylgeranyl pyrophosphate (GGPP), a substance essential for RhoA activation. In the present study, to investigate the effects of SF on fibrosis, portal hypertension and the RhoA/Rho-kinase pathway, hepatic cirrhosis was induced in rats by bile duct ligation. Liver function and fibrogenesis-related biochemical parameters, the hepatic hydroxyproline content, the pathological characteristics of the liver sections and the levels of hepatic α-smooth muscle actin (α-SMA; by immunohistochemistry) were analyzed to assess effects of SF on hepatic fibrosis. In addition, hepatic RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) expression was examined by immunohistochemistry. Apoptosis in the SF-treated and SF + GGPP-treated rat primary hepatic stellate cells (HSCs) and a human stellate cell line (LX-2) was examined by flow cytometry. Intrahepatic resistance and responsiveness to the α1-adrenoceptor agonist, methoxamine, were investigated by in situ liver perfusion. Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage. The SF-treated rats had a significantly lower expression of α-SMA and Rho-kinase, as well as an increased hepatic eNOS content; however, SF did not affect RhoA expression. The SF-treated HSCs had a significantly increased apoptotic rate compared to the untreated rats. Following the addition of GGPP, the rate apoptotic rate decreased. SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine. Therefore, our data demonstrate that SF reduces fibrogenesis, decreases portal pressure in cirrhotic rats and inhibits the activation of the RhoA/Rho-kinase signaling pathway.

Show MeSH
Related in: MedlinePlus