Rock-1基因在缺氧性肺动脉高压大鼠肺组织中的表达及法舒地尓的预防作用

Expression of Rock-1 mRNA in the lung tissue of the rats with hypoxic pulmonary hypertension and the preventive effects of fasudil

目的:观察小G蛋白Rho相关激酶(Rock-1)基因在大鼠缺氧性肺动脉高压(HPH)肺组织中的表达规律,探讨法舒地尔(fasudil)对HPH的预防作用。方法:72只SD大鼠随机分为缺氧模型组(H组)和缺氧+fasudil预防组(fasudil组),对照组(C组)。采用常压间断缺氧法复制大鼠HPH模型,右心导管测平均肺动脉压力(mPAP),计算右心室(RV)/[左心室+室间隔(LV+S)]的重量比值作为右心肥厚指数,并用RT-PCR方法测定肺组织Rock-1及平滑肌肌动蛋白(α-SMA)mRNA表达水平。结果:mPAP在缺氧7天后明显增高(P<0.01),并随缺氧时间的延长,进一步升高。右心肥厚指数在H组第7天开始升高,第14天与C组比较差异有显著性(P<0.01)。与H组比较,fasudil组mPAP及右心肥厚指数均明显降低(P<0.01)。Rock-1基因在HPH发生早期即明显上调,第7天达高峰后维持于较高水平。α-SMA基因表达第7天明显上调,第14天达高峰,至模型后期仍高于基础表达;Rock-1基因表达较α-SMA提前达到高峰,二者呈显著正相关(r=0.883,P<0.05);fasudil组两基因表达水平均较H组明显降低(P<0.01)。结论:Rock-1基因在HPH大鼠肺组织中出现了明显表达异常,法舒地尔能显著降低mPAP,改善右心室肥厚,并可能通过抑制肺组织Rock-1基因表达发挥作用。

Objective: To study the expression of Rock-1 mRNA in the lung tissue of the rats with hypoxic pulmonary hypertension (HPH) and to explore the preventive effects of fasudil. Methods: Seventy-two Spraque-Dawley male rats were randomly divided into hypoxia(H) group, hypoxia+fasudil(fasudil) group, and control(C) group. The rat model of HPH was established by exposing rats to normobaric intermittent hypoxic conditions. The pulmonary arterial pressure (mPAP) was measured by right-heart catheterization. The ratio of the right ventricle weight (RV) to left ventricle weight (LV) plus septum weight (S) RV/(LV+S) was measured and served as the index for right ventricular hypertrophy. The expression level of Rho kinase (Rock-1) and smooth muscle alpha-actin(α- SMA) mRNA were examined by RT-PCR in lung tissue. Results: The level of mPAP was significantly higher in H group than that in C group(P < 0.01) and it was much lower in fasudil group than that of H group(P < 0.01). The level of right ventricular hypertrophy was obviously lower in fasudil group than that in H group.The expression level of Rock-1 mRNA in H group was markedly up- regulated even before the onset of HPH (P < 0.01), and it was much lower in fasudil group compared with H group. The expression of Rock-1 gene was significantly positively correlated with that of α-SMA(r = 0.883, P < 0.05). Conclusion: Rock-1 may be involved in the mechanism of the progression of HPH. Fasudil can significantly decrease mPAP expression, and alleviate the right ventricular hypertrophy due to the inhibition of Rock-1 gene expression.