罗格列酮或氯沙坦及二者合用对大鼠血管损伤后再狭窄影响的研究

Effects of rosiglitazone, losartan and combined treatment on restenosis after thoracic aorta balloon injury in rats

目的对比罗格列酮或氯沙坦及二者合用对大鼠胸主动脉损伤后再狭窄的影响,并探讨其分子生物学机制。方法以球囊损伤方法建立大鼠胸主动脉损伤模型。雄性SD大鼠随机分成(1)假手术组,(2)罗格列酮组,(3)氯沙坦组,(4)罗格列酮+氯沙坦组,(5)损伤组。7d后光镜和HE染色观察血管管腔面积和内膜面积变化,以原位杂交方法检测基质金属蛋白酶9(MMP9)mRNA的表达,以免疫组化方法检测MMP9及磷酸化细胞外信号调节激酶1/2(pERK1/2)蛋白表达;术后4h,1d和7d,以放射免疫法检测血浆中肿瘤坏死因子α(TNFα)变化。结果罗格列酮+氯沙坦组明显抑制动脉再狭窄,抑制MMP9mRNA及蛋白表达以及pERK1/2蛋白表达,降低血浆中TNFα浓度。而罗格列酮组和氯沙坦组不能抑制动脉狭窄及MMP9和pERK1/2表达。结论罗格列酮与氯沙坦二者合用可以显著抑制大鼠主动脉损伤后再狭窄,降低MMP9及pERK1/2表达,使血浆中炎症因子减少。

Objective To investigate the effect of rosiglitazone,losartan and combined treatment on restenosis after rat's thoracic aorta balloon injury and to explore its molecular biology mechanism.Methods The rat model of thoracic aorta balloon injury was made by balloon injury method. Male SD rats were randomly divided into ①sham ligation, ②rosiglitazone, ③losartan, ④rosiglitazone+losartan and ⑤injury group. The thoracic aortas wall and intimal areas were observed with microscope and HE staining method at the 7th day after operation. The expressions of matrix metalloproteinase-9 (MMP-9) mRNA were determined by hybridization in situ, the protein expressions of MMP-9 and phosphate extracellular signal-regulated kinase1/2 (pERK1/2) were measured by immunohistochemical. The plasma tumor necrosis factor-α(TNF-α) levels were detected with radioimmunoassay at 4 h, 1 and 7 d after operation.Results Combination of rosiglitazone and losartan significantly inhibited lumen restenosis, decreased MMP-9 mRNA expression and pERK1/2 and MMP-9 protein expression, reduced plasma TNF-αlevel. But rosiglitazone and losartan could not inhibit lumen restenosis, MMP-9 and pERK1/2 expression alone.Conclusions Combination of rosiglitazone and losartan could significantly inhibit aorta restenosis, decrease expression of MMP-9 and pERK1/2 and reduce the level of plasma cytokine.