辛伐他汀通过抑制p38 MAPK活化降低肝硬化门静脉高压大鼠门静脉压力

 目的:探讨p38 MAPK信号通路在辛伐他汀降低肝硬化门静脉高压症大鼠门静脉压力（PP）中的作用。方法:采用四氯化碳复合因素法构建大鼠肝硬化门静脉高压症模型,成模后将存活大鼠随机分为模型组（n=10）、辛伐他汀治疗组（n=11）和p38 MAPK信号通路抑制剂SB203580处理组（n=10）,后2组分别给予辛伐他汀及SB203580干预处理;另设正常对照组（n=8）。处理结束后检测大鼠PP、肝脏总p38 MAPK蛋白、磷酸化p38 MAPK蛋白、总eNOS蛋白、磷酸化eNOS蛋白表达水平以及肝脏一氧化氮（NO）含量的变化。结果:（1）模型组大鼠PP明显高于正常对照组;辛伐他汀治疗组及SB203580处理组PP均明显低于模型组（P＜0.01）,辛伐他汀治疗组PP明显低于SB203580处理组（P＜0.01）。（2）与正常大鼠相比,模型组大鼠肝脏总p38 MAPK蛋白及总eNOS蛋白表达水平无明显变化（P＞0.05）,而磷酸化p38 MAPK蛋白及磷酸化eNOS蛋白表达水平分别增高与降低（P＜0.01）;辛伐他汀治疗组大鼠肝脏磷酸化p38 MAPK蛋白及磷酸化eNOS蛋白表达水平分别降低与增高（P＜0.01）;SB203580处理组大鼠肝脏磷酸化p38 MAPK蛋白及磷酸化eNOS蛋白表达水平分别降低与增高（P＜0.01）,但磷酸化eNOS蛋白表达水平增高的程度低于辛伐他汀治疗组（P＜0.01）。(3)辛伐他汀治疗组肝脏NO含量［（15.73±1.59） μmol/(g protein)］及SB203580处理组肝脏NO含量［（13.98±1.27) μmol/(g protein)］明显高于模型组［（9.81±1.12） μmol/（g protein）］（P＜0.01）,辛伐他汀治疗组NO含量明显高于SB203580处理组（P＜0.01）。结论: 辛伐他汀降低肝硬化门静脉高压症大鼠门静脉压力可能与其抑制p38 MAPK信号通路的活化有关。

Simvastatin lowers portal pressure in rats with cirrhosis and portal hypertension via inhibiting activation of p38 MAPK signaling pathway

AIM: To investigate the role of p38 MAPK signaling pathway in the course of simvastatin-induced portal pressure (PP) reduction in the rats with cirrhosis and portal hypertension. METHODS: The rat model of cirrhosis and portal hypertension was induced by treating the animals with composite factors including carbon tetrachloride. These model rats were randomly divided into model group (n=10), simvastatin treatment group (n=11) and SB203580, treatment group (n=10). The rats in the latter 2 groups were treated with simvastatin and p38 MAPK inhibitor SB203580, respectively. Another eight normal rats served as normal controls. After the end of treatment, the PP of the model rats was measured and total p38 MAPK protein, phosphorylated p38 MAPK protein, total endothelial nitric oxide synthase (eNOS) protein, phosphorylated eNOS protein, and nitric oxide(NO) content in the livers were analyzed. RESULTS: The PP of the rats in model group was significantly higher than that in normal control group. The PP of the rats in both simvastatin treatment group and SB203580 treatment group was significantly lower than that in model group, and the PP of the rats in simvastatin treatment group was lower than that in SB203580 treatment group. No significant change of  total p38 MAPK protein and total eNOS protein between normal group and model group was observed. Compared with normal control group, the expression levels of phosphorylated p38 MAPK protein increased and phosphorylated eNOS protein decreased in model group.Compared with model group, the expression levels of phosphorylated p38 MAPK protein decreased and phosphorylated eNOS protein increased in simvastatin treatment group and SB203580 treatment group. The increase in the expression level of phosphorylated eNOS protein in SB203580 treatment group was lower than that in simvastatin treatment group. The hepatic NO content in simvastatin treatment group and SB203580 treatment group was significantly higher than that in model group, and that in simvastatin treatment group was higher than that in SB203580 treatment group. CONCLUSION: Simvastatin lowers PP in the rats with cirrhosis and portal hypertension by inhibiting the activation of p38 MAPK signaling pathway.