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

Wei,Lai; Yang,Juan; Wang,Min; Xu,Sheng-Nan; Liang,Hua-Min; Zhou,Qi

doi:10.3892/ijmm.2014.1905

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

Authors:
- Lai Wei
- Juan Yang
- Min Wang
- Sheng-Nan Xu
- Hua-Min Liang
- Qi Zhou
View Affiliations

Affiliations: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China, Department of Digestive Diseases, Chengdu First People's Hospital, Chengdu, Sichuan, P.R. China, Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China, Department of Digestive Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China, Department of Physiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
Published online on: August 19, 2014 https://doi.org/10.3892/ijmm.2014.1905
Pages: 1257-1267
Copyright: © Wei et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Hennenberg M, Biecker E, Trebicka J, et al: Defective RhoA/Rho-kinase signaling contributes to vascular hypocontractility and vasodilation in cirrhotic rats. Gastroenterology. 130:838–854. 2006. View Article : Google Scholar : PubMed/NCBI
2	Zhou Q, Hennenberg M, Trebicka J, et al: Intrahepatic upregulation of RhoA and Rho-kinase signalling contributes to increased hepatic vascular resistance in rats with secondary biliary cirrhosis. Gut. 55:1296–1305. 2006. View Article : Google Scholar : PubMed/NCBI
3	Bari K and Garcia-Tsao G: Treatment of portal hypertension. World J Gastroenterol. 18:1166–1175. 2012. View Article : Google Scholar
4	Miñano C and Garcia-Tsao G: Clinical pharmacology of portal hypertension. Gastroenterol Clin North Am. 39:681–695. 2010.
5	van Beuge MM, Prakash J, Lacombe M, et al: Reduction of fibrogenesis by selective delivery of a Rho kinase inhibitor to hepatic stellate cells in mice. J Pharmacol Exp Ther. 337:628–635. 2011.PubMed/NCBI
6	Ikeda H, Nagashima K, Yanase M, et al: Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 285:G880–G886. 2003.PubMed/NCBI
7	Sohail MA, Hashmi AZ, Hakim W, et al: Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition. Hepatology. 49:185–194. 2009. View Article : Google Scholar : PubMed/NCBI
8	van Beuge MM, Prakash J, Lacombe M, Post E, Reker-Smit C, Beljaars L and Poelstra K: Increased liver uptake and reduced hepatic stellate cell activation with a cell-specific conjugate of the Rho-kinase inhibitor Y27632. Pharm Res. 28:2045–2054. 2011.PubMed/NCBI
9	Trebicka J, Hennenberg M, Laleman W, et al: Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology. 46:242–253. 2007. View Article : Google Scholar : PubMed/NCBI
10	Anegawa G, Kawanaka H, Yoshida D, et al: Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis. Hepatology. 47:966–977. 2008. View Article : Google Scholar : PubMed/NCBI
11	Brandão DF, Ramalho LN, Ramalho FS, Zucoloto S, de Martinelli AL and de Silva OC: Liver cirrhosis and hepatic stellate cells. Acta Cir Bras. 21(Suppl 1): S54–S57. 2006.
12	Chakraborty JB, Oakley F and Walsh MJ: Mechanisms and biomarkers of apoptosis in liver disease and fibrosis. Int J Hepatol. 2012:6489152012. View Article : Google Scholar : PubMed/NCBI
13	Cichoz-Lach H, Celinski K, Slomka M and Kasztelan-Szczerbinska B: Pathophysiology of portal hypertension. J Physiol Pharmacol. 59(Suppl 2): S231–S238. 2008.
14	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
15	Charlton-Menys V and Durrington PN: Human cholesterol metabolism and therapeutic molecules. Exp Physiol. 93:27–42. 2008. View Article : Google Scholar
16	Lee MH, Cho YS and Han YM: Simvastatin suppresses self-renewal of mouse embryonic stem cells by inhibiting RhoA geranylgeranylation. Stem Cells. 25:1654–1663. 2007. View Article : Google Scholar : PubMed/NCBI
17	Schmidmaier R, Baumann P, Simsek M, Dayyani F, Emmerich B and Meinhardt G: The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase. Blood. 104:1825–1832. 2004. View Article : Google Scholar : PubMed/NCBI
18	Martinez-Sales V, Vila V, Ferrando M and Reganon E: Atorvastatin neutralises the thrombin-induced tissue factor expresion in endothelial cells via geranylgeranyl pyrophosphate. Cytotechnology. 63:1–5. 2011. View Article : Google Scholar
19	Luo W, Meng Y, Ji HL, et al: Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat. PLoS One. 7:e342302012. View Article : Google Scholar : PubMed/NCBI
20	Piao RL, Brigstock DR, Zhu J, Zhang ML and Gao RP: Clinical significance of connective tissue growth factor in hepatitis B virus-induced hepatic fibrosis. World J Gastroenterol. 18:2280–2286. 2012. View Article : Google Scholar : PubMed/NCBI
21	Xu Q, Liu X, Chen W and Zhang Z: Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference. J Transl Med. 8:1362010. View Article : Google Scholar : PubMed/NCBI
22	Jiroutová A, Majdiaková L, Cermáková M, Köhlerová R and Kanta J: Expression of cytoskeletal proteins in hepatic stellate cells isolated from normal and cirrhotic rat liver. Acta Medica (Hradec Kralove). 48:137–144. 2005.PubMed/NCBI
23	Kim KY, Choi I and Kim SS: Purification and characterization of a novel inhibitor of the proliferation of hepatic stellate cells. J Biochem. 127:23–27. 2000. View Article : Google Scholar : PubMed/NCBI
24	Olaso E, Arteta B, Benedicto A, Crende O and Friedman SL: Loss of discoidin domain receptor 2 promotes hepatic fibrosis after chronic carbon tetrachloride through altered paracrine interactions between hepatic stellate cells and liver-associated macrophages. Am J Pathol. 179:2894–2904. 2011. View Article : Google Scholar
25	March S, Graupera M, Rosa Sarrias M, Lozano F, Pizcueta P, Bosch J and Engel P: Identification and functional characterization of the hepatic stellate cell CD38 cell surface molecule. Am J Pathol. 170:176–187. 2007. View Article : Google Scholar : PubMed/NCBI
26	Vairetti M, Richelmi P, Bertè F, Currin RT, Lemasters JJ and Imberti R: Role of pH in protection by low sodium against hypoxic injury in isolated perfused rat livers. J Hepatol. 44:894–901. 2006. View Article : Google Scholar : PubMed/NCBI
27	Kukan M, Szatmáry Z, Lutterová M, Kuba D, Vajdová K and Horecký J: Effects of sizofiran on endotoxin-enhanced cold ischemia-reperfusion injury of the rat liver. Physiol Res. 53:431–437. 2004.PubMed/NCBI
28	Vairetti M, Ferrigno A, Carlucci F, et al: Subnormothermic machine perfusion protects steatotic livers against preservation injury: a potential for donor pool increase? Liver Transpl. 15:20–29. 2009. View Article : Google Scholar
29	Kim MY, Baik SK and Lee SS: Hemodynamic alterations in cirrhosis and portal hypertension. Korean J Hepatol. 16:347–352. 2010. View Article : Google Scholar : PubMed/NCBI
30	Reynaert H, Urbain D and Geerts A: Regulation of sinusoidal perfusion in portal hypertension. Anat Rec (Hoboken). 291:693–698. 2008. View Article : Google Scholar : PubMed/NCBI
31	Al-Busafi SA, McNabb-Baltar J, Farag A and Hilzenrat N: Clinical manifestations of portal hypertension. Int J Hepatol. 2012:2037942012.PubMed/NCBI
32	Bishop AL and Hall A: Rho GTPases and their effector proteins. Biochem J. 348:241–255. 2000. View Article : Google Scholar : PubMed/NCBI
33	Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X and Surks HK: ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 104:531–540. 2009. View Article : Google Scholar : PubMed/NCBI
34	Ho JH and Hong CY: Salvianolic acids: small compounds with multiple mechanisms for cardiovascular protection. J Biomed Sci. 18:302011. View Article : Google Scholar : PubMed/NCBI
35	Xu H, Zhou Y, Lu C, Ping J and Xu LM: Salvianolic acid B lowers portal pressure in cirrhotic rats and attenuates contraction of rat hepatic stellate cells by inhibiting RhoA signaling pathway. Lab Invest. 92:1738–1748. 2012. View Article : Google Scholar : PubMed/NCBI
36	Ardiansyah, Ohsaki Y, Shirakawa H, Koseki T and Komai M: Novel effects of a single administration of ferulic acid on the regulation of blood pressure and the hepatic lipid metabolic profile in stroke-prone spontaneously hypertensive rats. J Agric Food Chem. 56:2825–2830. 2008. View Article : Google Scholar
37	Huang Z, Wei W and Zhong Q: Effect of sodium ferulate on hemodynamics in hepatic cirrhosis patients with portal hypertension. Zhongguo Zhong Xi Yi Jie He Za Zhi. 28:640–642. 2008.(In Chinese).
38	Dudzinski DM and Michel T: Life history of eNOS: partners and pathways. Cardiovasc Res. 75:247–260. 2007. View Article : Google Scholar : PubMed/NCBI
39	Shiga N, Hirano K, Hirano M, Nishimura J, Nawata H and Kanaide H: Long-term inhibition of RhoA attenuates vascular contractility by enhancing endothelial NO production in an intact rabbit mesenteric artery. Circ Res. 96:1014–1021. 2005. View Article : Google Scholar : PubMed/NCBI
40	Uehara H, Akahoshi T, Kawanaka H, et al: Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis. Hepatol Res. 42:1039–1047. 2012. View Article : Google Scholar : PubMed/NCBI
41	Verbeke L, Farre R, Trebicka J, et al: Obeticholic acid, a farnesoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology. Nov 20–2013.(Epub ahead of print). View Article : Google Scholar
42	Meng LQ, Tang JW, Wang Y, et al: Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy. Br J Pharmacol. 162:1805–1818. 2011. View Article : Google Scholar : PubMed/NCBI
43	Alam MA, Sernia C and Brown L: Ferulic acid improves cardiovascular and kidney structure and function in hypertensive rats. J Cardiovasc Pharmacol. 61:240–249. 2013. View Article : Google Scholar : PubMed/NCBI
44	Kim HY, Park J, Lee KH, Lee DU, Kwak JH, Kim YS and Lee SM: Ferulic acid protects against carbon tetrachloride-induced liver injury in mice. Toxicology. 282:104–111. 2011. View Article : Google Scholar : PubMed/NCBI
45	Rukkumani R, Aruna K, Suresh Varma P and Padmanabhan Menon V: Hepatoprotective role of ferulic acid: a dose-dependent study. J Med Food. 7:456–461. 2004. View Article : Google Scholar : PubMed/NCBI
46	Xu X, Xiao H, Zhao J and Zhao T: Cardioprotective effect of sodium ferulate in diabetic rats. Int J Med Sci. 9:291–300. 2012. View Article : Google Scholar : PubMed/NCBI
47	Wang BH and Ou-Yang JP: Pharmacological actions of sodium ferulate in cardiovascular system. Cardiovasc Drug Rev. 23:161–172. 2005. View Article : Google Scholar : PubMed/NCBI
48	Lowyck I and Fevery J: Statins in hepatobiliary diseases: effects, indications and risks. Acta Gastroenterol Belg. 70:381–388. 2007.PubMed/NCBI
49	Lin Z, Gu J, Xiu J, Mi T, Dong J and Tiwari JK: Traditional chinese medicine for senile dementia. Evid Based Complement Alternat Med. 2012:6926212012.PubMed/NCBI
50	Holmberg B, Brännström M, Bucht B, Crougneau V, Dimeny E, Ekspong A, Granroth B, Gröntoft KC, Hadimeri H, Ingman B, Isaksson B, Johansson G, Lindberger K, Lundberg L, Mikaelsson L, Olausson E, Persson B, Welin D, Wikdahl AM and Stegmayr BG: Safety and efficacy of atorvastatin in patients with severe renal dysfunction. Scand J Urol Nephrol. 39:503–510. 2005. View Article : Google Scholar : PubMed/NCBI