Rho激酶抑制剂对压力超负荷大鼠心肌纤维化的影响

目的:观察Rho激酶抑制剂法舒地尔对大鼠心肌纤维化的影响。方法:采用腹主动脉缩窄术制备SD大鼠心肌纤维化模型,动脉夹闭4周后,随机分为4组:假手术组(Sham组)、模型组(Model组)、法舒地尔高剂量(FH,30mg/Kg/天)组和法舒地尔低剂量(FL,10mg/Kg/天)组。术后8周末,计算各组大鼠心脏质量指数(HWI)、左室质量指数(LVWI),观察心肌组织HE染色和Masson染色,碱水解法测定心肌组织羟脯氨酸(HYP)含量,免疫组化分析磷酸化的肌球蛋白磷酸酶靶蛋白亚基1(p-MYPT1)、转化生长因子β1(TGF-β1)和结缔组织生长因子(CTGF)水平。结果:与Sham组相比,Model组大鼠LVWI及HYP含量显著升高(P<0.01),心肌细胞排列紊乱,间质大量胶原纤维沉积,心肌组织p-MYPT1水平升高(P<0.01),TGF-β1、CTGF表达升高(P<0.01);与Model组相比,FH组和FL组大鼠LVWI及HYP含量降低(P<0.05),间质胶原蛋白沉积程度减轻,心肌组织p-MYPT1、TGF-β1、CTGF水平均降低(P<0.05或P<0.01)。结论:Rho激酶参与压力超负荷诱导的大鼠心肌纤维化,法舒地尔抑制心肌纤维化进展的作用与TGF-β1和CTGF水平的降低有关。

The Effects of Rho Kinase Inhibitor on Cardiac Fibrosis in Pressure-overload Rats

Objective: To investigate the effects of fasudil, a Rho kinase inhibitor, on cardiac fibrosis in pressure-overload rats. Method: The SD rats were prepared with abdominal aorta constriction and fed under standard condition. The abdominal aortas were clipped for 4 weeks. These rats were divided into 4 groups randomly: sham group, model group, fasudil high-dose group (FH, 30mgKgd) and fasudil low-dose group (FL, 10mgKgd). At 8 weeks after surgery, the left ventricleweight index (LVWI) were calculated, and the content of cardiac hydroxyproline (HYP) was measured using alkaline hydrolysis. Myocardial histopathology and interstitial fibrosis were detected with HE and Masson staining. Transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were analyzed with immunohistochemistry. Results: Comparing with sham group, the LVWI and HYP content were significantly elevated in model group (P<0.01). Much more collagen deposited in myocardial interstitium. Rho kinase activity was significantly elevated, associated with increased TGF-β1 and CTGF(P<0.01). Comparing with the model group, fasudil reduced the LVWI and HYP content, and reduced interstitial collagen deposition. Rho kinase activity was significantly decreased associated with much lower expression of TGF-β1 and CTGF (P<0.05). Conclusion: Rho kinase plays an important role in abdominal aortic constriction induced myocardial fibrosis. Decreased TGF-β1 and CTGF partly contribute to the protective effect of fasudil on heart against pressure-overload.