雌激素受体β激动剂对肝硬化门静脉高压大鼠高动力循环的调节作用及其机制

Effects and mechanism of estrogen receptor beta agonist on hyperdynamic circulation in cirrhotic rats with portal hypertension

目的通过研究雌激素受体β(ERβ)激动剂二芳基丙腈(DNP)对肝硬化门静脉高压症(PHT)大鼠肠系膜动脉(MA)反应性和Rho激酶信号通路的影响,阐述DNP在肝硬化门静脉高压症大鼠内脏高动力循环中的作用机制。方法雌性大鼠行双侧卵巢切除术,并采用四氯化碳注射创建肝硬化PHT模型。分组干预后检测各组血流动力学参数、MA血管反应性,并检测各组大鼠MA中ERβ、Rho激酶信号通路相关蛋白和受体脱敏相关蛋白的表达。结果DNP能明显改善去势肝硬化大鼠的血流动力学参数,提高MA对去甲肾上腺素的反应性,提高受抑制的ROCK蛋白的激活作用,并下调β-arrestin-2的表达和ERK1/2的磷酸化水平。结论DNP能提高MA对缩血管物质的反应性,明显改善去势肝硬化大鼠的高动力循环状态。该效应可能与DNP改善MA对缩血管物质的受体脱敏现象,从而激活Rho激酶通路有关。

Objective To investigate the effects of estrogen receptor beta agonist diarylpropionitrile(DPN)on mesenteric artery(MA)responsiveness and on Rho-kinase signaling pathway in cirrhotic portal hypertension rats,and to elucidate the mechanism of ER beta agonist in visceral hyperdynamic circulation in cirrhotic portal hypertension rats.Methods Female rats were treated with bilateral ovariectomy,and CCl4 was injected to establish cirrhotic portal hypertension model.After intervention,hemodynamic parameters and vascular reactivity of MA in each group were measured,and the levelof ER beta,Rho-kinase signaling pathway-related proteins and receptor desensitization-related proteins in MA in each group were detected.Results DPN could significantly improve the hemodynamic parameters of ovariectomized cirrhosis rats and the response of MA to norepinephrine.DPN could increase the level of inhibited ROCK protein and decrease the expression of beta-arrestin-2 and the phosphorylation of ERK1/2.Conclusions DPN could improve the responsiveness of MA to vasoconstrictor substances,and significantly improve the hyperdynamic circulation in ovariectomized cirrhosis rats.This effect may be related to DPN improving the desensitization of MA to vasoconstrictor receptors and the Rho-kinase pathway activation.