白藜芦醇可改​​善肝硬化大鼠肝内血管内皮功能障碍，降

StephenW

Journal of Hepatology

Volume 58, Issue 5, May 2013, Pages 904–910

Research Article
Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats

    Marco Di Pascoli†,
    Marta Diví†,
    Aina Rodríguez-Vilarrupla,
    Eugenio Rosado,
    Jorge Gracia-Sancho,
    Marina Vilaseca,
    Jaume Bosch,
    Joan Carles García-PagánCorresponding author contact information, E-mail the corresponding author

    Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain

    http://dx.doi.org/10.1016/j.jhep.2012.12.012, How to Cite or Link Using DOI

   
Background & Aims

Resveratrol, a polyphenol found in a variety of fruits, exerts a wide range of beneficial effects on the endothelium, regulates multiple vasoactive substances and decreases oxidative stress, factors involved in the pathophysiology of portal hypertension. Our study aimed at evaluating the effects of resveratrol on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats.
Methods

Resveratrol (10 and 20 mg/kg/day) or its vehicle was administered to cirrhotic rats for two weeks and hepatic and systemic hemodynamics were measured. Moreover, we evaluated endothelial function by dose-relaxation curves to acetylcholine, hepatic NO bioavailability and TXA2 production. We also evaluated liver fibrosis by Sirius Red staining of liver sections, collagen-1, NFκB, TGFβ mRNA expression, and desmin and α-smooth muscle actin (α-SMA) protein expression, as a surrogate of hepatic stellate cell activation.
Results

Resveratrol administration significantly decreased portal pressure compared to vehicle (12.1 ± 0.9 vs. 14.3 ± 2.2 mmHg; p <0.05) without significant changes in systemic hemodynamics. Reduction in portal pressure was associated with an improved vasodilatory response to acetylcholine, with decreased TXA2 production, increased endothelial NO, and with a significant reduction in liver fibrosis. The decrease in hepatic fibrosis was associated with a reduced collagen-1, TGFβ, NFκB mRNA expression and desmin and α-SMA protein expression.
Conclusions

Resveratrol administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis.
Abbreviations

    NO, nitric oxide;
    COX-1, cyclooxygenase-1;
    eNOS, endothelial nitric oxide synthase;
    CCl4, carbon tetrachloride;
    MAP, mmHg, mean arterial pressure;
    PP, mmHg, portal pressure;
    PBF, ml min−1, portal blood flow;
    SMABF, ml min−1, superior mesenteric artery blood flow;
    Mtx, methoxamine;
    Ach, acetylcholine;
    TXB2, thromboxane B2;
    View the MathML sourceO2-, superoxide;
    DHE, dihydroethidium;
    cGMP, cyclic guanosine monophosphate;
    P-eNOS, phosphorylated eNOS;
    α-SMA, α smooth muscle actin

Keywords

    Oxidative stress;
    Endothelial dysfunction;
    Nitric oxide;
    Thromboxane

StephenW

背景与目的

各种水果中发现的一种多酚，白藜芦醇，发挥有利影响广泛的内皮，调节多种血管活性物质，降低氧化应激，门静脉高压症的病理生理因素。我们的研究旨在评估白藜芦醇对肝功能和全身血流动力学，肝血管内皮功能障碍，四氯化碳肝硬化大鼠肝纤维化。
方法

白藜芦醇（10和20毫克/公斤/天）或它的车辆的两个星期，肝，肝硬化大鼠给药全身血流动力学测定。此外，我们评估了血管内皮功能的剂量松弛曲线乙酰胆碱，肝NO的生物利用度和TXA2生产。我们也评估了天狼红染色的肝切片，胶原蛋白-1，NFκB，TGF-βmRNA的表达，结蛋白（desmin），α-平滑肌肌动蛋白（α-SMA）蛋白表达的肝纤维化，作为替代的肝星状细胞的活化。
结果

白藜芦醇管理显着降低门脉压力相比，没有显着变化，全身血流动力学的车辆（12.1±0.9比14.3±2.2毫米汞柱，P <0.05）。降低门静脉压力与一种改进的对乙酰胆碱的血管舒张反应，减少TXA2的生产，增加内皮一氧化氮，并具有显着降低肝纤维化。肝纤维化的减少是与减少胶原-1，TGFβ，NFκBmRNA的表达与结蛋白和α-SMA蛋白表达。
结论

白藜芦醇管理降低门静脉压力，肝星状细胞的活化和肝纤维化，改善肝硬化大鼠的肝血管内皮功能障碍，暗示它可能是一个有用的治疗门静脉高压症，肝硬化患者的膳食补充剂。
缩略语