Effects And Mechanisms Of Sodium Ferulate On Portal Pressure In Cirrhotic Rats Via RhoA/Rho-kinase Signaling Pathway

Background and aims: Portal hypertension is one of the main factors leads to highmortality among patients with liver cirrhosis. Liver of experimental cirrhotic rats representhigher expression of RhoA and Rho-kinase compared with normal rats. Activation ofRhoA/Rho-kinase signaling pathway leads to portal hypertension by promotingconstriction of vascular smooth muscle, as well as inhibiting its relaxation. Studies havepreviously reported that sodium ferulate (SF) is effective in lowering cholesterol synthesis,and GGPP, the intermediate products of this synthesis process, is the Key material of RhoAactivation. The aim of our study was to investigate the effect of SF in cirrhotic rats withportal hypertension and some related molecular mechanism.Methods: Cirrhosis of experiment rats was induced by bile duct ligation. Rats weredivided into three groups: Group SHAM+NS, BDL+NS and BDL+SF. Compare generalcharacteristics and biochemical parameters between groups. Pathological characteristics ofliver sections observed by optical microscope and transmission electron microscope, anddetection of hepatic α-SMA content by immunohistochemistry were analyzed to assesseffect of sodium ferulate on hepatic fibrosis. Hepatic RhoA, Rho-kinase and eNOSexpressions were studied by immunohistochemistry. Flow cytometry was performed tocompare the apoptosis rate between SF-treated and SF+GGPP treated rat primary HSC andLX-2. Intrahepatic resistance and responsiveness of the α1-adrenoceptor agonistmethoxamine on that resistance between groups were investigated by in situ liverperfusion. Results: Body weight of cirrhotic rats was lower than Group SHAM+NS; liver and spleenweight, hepatic biochemical parameters except ALB of cirrhotic rats were significantlyhigher than Group SHAM+NS, those parameters did not differ between SF-treated anduntreated cirrhotic rats(P＞0.05). Pathological observation reveals that, the fibrosis degreeand hepatocyte damage are lower in cirrhotic rats treated by SF. Hepatic a-SMA、RhoA、Rho-kinase and eNOS content were significantly higher than Group SHAM+NS. SFtreated cirrhotic rats had significantly lower expression of α-SMA and Rho-kinase(P＜0.05vs. P＜0.05), reversely hepatic eNOS content increased(P＜0.05). SF did not affectexpression of RhoA(P＞0.05). Flow cytometric analysis showed that the apoptosis rate ofprimary HSCs and LX-2significantly increased as the content of SF increased(P＜0.01between adjacent groups); after adding GGPP, the apoptosis rate of group with40μg/ml SFremained(P＞0.05); the apoptosis rate of group with120μg/ml and360μg/ml SF reducedcompared with before(P＜0.05vs. P＜0.05). SF reduced basal intrahepatic resistance(P＜0.05) and responsiveness of methoxamine on hepatic vascular smooth muscle(P＜0.05).Conclusions: SF reduces fibrogenesis of cirrhotic rats. SF down-regulates hepaticRhoA/Rho-kinase signaling pathway, thus activation of HSCs and contraction of vascularsmooth muscle are inhibited; and eNOS synthesis inhibition caused by RhoA/Rho-kinasepathway is relieved, ultimately portal pressure decreases.