卡维地洛对异丙肾上腺素诱导大鼠心肌重塑中Rho/Rock信号通路的影响

目的研究卡维地洛对异丙肾上腺素诱导大鼠心肌重塑中的作用及对Rho/Rock信号通路的影响。方法 24只雄性SD大鼠随机分成3组:空白对照组(对照组)、ISO模型组(模型组)、卡维地洛(Carvedilol Car)组(治疗组),每组8只。模型组和治疗组皮下多点注射ISO[5 mg/(kg·d)×10 d]建立大鼠心肌纤维化模型,其中治疗组给予Car[10 mg/(kg·d)]灌胃,模型组及对照组每日给予相同体积的生理盐水灌胃。6周后取左室心肌组织进行MASSON染色、免疫组织化学染色,分别检测胶原容积分数(CVF)、心肌组织中转化生长因子-β1(TGF-β1)表达量;RT-PCR法检测心肌组织RhoA和Rho激酶(Rock)mRNA的表达。结果与对照组比较,模型组大鼠CVF增加,TGF-β1表达增高(P<0.01),左室组织RhoA和Rho激酶mRNA表达上调(P<0.01);与模型组比较,治疗组CVF表达下降(P<0.01),TGF-β1、RhoA和Rho激酶mRNA表达减少(P<0.01),但均仍高于对照组(P<0.01)。结论 ISO诱导心肌纤维化伴有Rho/Rock信号通路激活,卡维地洛能抑制Rho/Rock信号转导通路的活性、抑制TGF-β1表达,减轻心肌纤维化。

Objective To investigate the effect of Carvedilol on RhoA/Rock signaling pathway in cardiac fibrosis induced by isoproterenol （ISO） in rats and its mechanisms.Methods Twenty four SD rats were randomly divided into control group, ISO model group and Carvedilol （Car）group（therapy group）, 8 rats in each group. Cardiac fibrosis models were induced by subcutaneous injection of ISO[5 mg/（kg·d）]except for control group, Meanwhile, Therapy group were administrated by Carl10 mg/（kg·d）], and rats in the other two groups were given equal saline. After 6 weeks, the cross serial transverse sections of left ventricle （LV） of the rats were examined microscopically for collagen volume fraction （CVF） and transforming growth factorβ1 （TGF-β1） protein using an image analysis computer system after Masson staining and TGF-β1-antibody immunohistochemistry（IHC） staining respectively. RhoA and Rho kinase mRNA were tested by RT-PCR.Resuits Compared with those of control group, the expression levels of the protein of TGF-β1 and RhoAmRNA and Rho kinase mRNA increased in ISO model group（P〈0.01）. However, CVF（P 〈 0.01）, the protein of TGF-β1, the expression levels of RhoA and Rho kinase mRNAwere lower in Therapy group than in ISO model group （P〈 0.01）.There were some degree of improvements in all parameters. Conclusion Rho/Rho kinase signaling pathway may play an important role in myocardial fibrosis induced by ISO, and carvedilol can improve the pathological changes, which is associated with the inhibition of RhoA/Rho kinase signaling pathway and down-regulation of TGF-β1 expression level.