| Part I: preparation of portal hypertension rat modelAim: to prepare a stable and reliable rat model of portal hypertension(PHT).Methods: partial portal vein ligation(PPVL)was used to induce prehepatic portal hypertension model in rats.The intrahepatic portal hypertension rat model was induced by 50%CC4 subcutaneous injection.Results: the epidermis of CCl4 model rats was flabby and dry,and the surface nodules of the liver were obvious,with obvious cirrhosis,increased portal vein pressure,lower average arterial pressure,and slightly varicose internal blood vessels.There was no abnormality in the hair of PPVL model rats.The liver cirrhosis was not obvious.The portal vein pressure was increased,and the average arterial pressure was decreased,and the internal organs were thickened and the varicose veins were serious.Conclusion: the two molding methods are stable and reliable,and the effect of molding is good.PPVL model is suitable for the study of portal hypertension internal circulation,and CCl4 model is suitable for the study of intrahepatic lesions.Part II: the role of epoxyeicosatrienoic acids in cirrhotic portal hypertension in ratsAim: to explore the effect of epoxyeicosatrienoic acids(EETs)on PHT rats.Methods: The s EH inhibitor,t-TUCB(trans-4-benzoic acid)was administered to stabilize hepatic EETs by gavage at a dose of 1 mg/kg/d.Hemodynamics,liver fibrosis were evaluated.Results: after t-TUCB treatment,the content of EETs in the PHT rats increased,and portal pressure and liver fibrosis were attenuated.Conclusion: EETs can alleviate portal hypertension and cirrhosis in rats.Our results indicates that s EH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis.Part III: the mechanism of EETs reducing portal pressure in PHT with liver cirrhosis in ratsAim: To explore the mechanism of inhibition of s EH reducing portal pressure in PHT with liver cirrhosis.Methods: Evaluation of endothelial function was performed by in-situ perfusion in liver.The expression of endothelial nitric oxide synthase(e NOS),pe NOS(phosphorylation-e NOS),Caveolin-1,NF-?B,and NO content were detected.In vitro LX2 proliferation was performed,and primary HSCs activation was evaluated by detection of ?-SMA.Results: after t-TUCB treatment,the function of the intrahepatic vessels was improved,which was manifested as the improvement of acetylcholine diastolic.The level of e NOS phosphorylation in the liver was increased,and Caveolin-1 expression was decreased.NO content in liver was increased after rats receving t-TUCB.EETs inhibited LX2 proliferation via concentration-dependent way,and inhibited the expression of ?-SMA of parimary HSCs in vitro.Conclusion: t-TUCB enhances e NOS phosphorylation and NO production in endothelial cells,thereby alleviating the dysfunction of endothelial function in the liver and reducing intrahepatic vascular resistance.T-TUCB inhibits hepatic fibrosis/cirrhosis through hepatic stellate cell activation and NF-?B signaling pathway.Part IV: the role of NOX1/4 in portal hypertension in rtasAim: to investigate the role of NADPH oxidase(NOX)in rat portal hypertension.Methods: using the NOX1/4 inhibitor GKT137831 to treat the PPVL induced PHT model in rats.The portal vein pressure,cardiac output,portal vein blood flow,portal flow rate and portal vein flow resistance were detected in rats.Results: GKT137831 decreased the portal vein pressure,cardiac output,portal vein flow and portal vein flow rate in PPVL rats,and increased the flow resistance of portal vein.Conclusion: inhibition of NOX1/4 can effectively attenuate the portal hypertension of PHT.Part V: the mechanisms of inhibition of NOX1/4 improving of portal hypertension in ratsAim: to explore the mechanism of inhibition of NADPH oxidase(NOX)to attenuate portal hypertension in rats.Methods: the contractility,oxidative stress and AKT/e NOS phosphorylation level of the mesenteric artery in PHT rats were detected.The expression of VEGF,VEGFR-2 and CD31 in the mesenteric tissue of PHT rats was detected.Results: the NOX1/4 inhibitor GKT137831 enhanced the contractility of the mesenteric artery of the PHT,reduced the oxidative stress level of the artery and the phosphorylation level of AKT/e NOS;GKT137831 reduced the expression of mesenteric tissue CD31,VEGF and VEGFR-2.Conclusion: GKT137831 inhibits VEGF-dependent visceral angiogenesis,inhibits oxidative stress,and improves the contractility of mesenteric artery through the AKT/e NOS signaling pathway,and finally attenuates the portal hypertension of PHT rats. |
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