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目的探讨血管紧张素转换酶抑制剂卡托普利逆转阿霉素心肌病大鼠左室重构和改善心功能的作用机制。方法雄性Wistar大鼠分3组:(1)阿霉素心肌病组(ADR-DCM组,25只):阿霉素2．5 mg／kg,尾静脉注射,每周1次,连续10周;(2)ADR-DCM+卡托普利治疗组(ACEI组,25只):卡托普利50 mg·kg-1·d-1灌胃治疗;(3)健康对照组(对照组,10只)。阿霉素注射2周后行超声和血流动力学检测,硫代巴比妥酸法检测丙二醛(MDA)含量,苦味酸天狼星红染色进行左室胶原特异染色及定量分析,计算胶原容积分数(CVF),RT-PCR检测金属基质蛋白酶(MMP)-2、MMP-9及金属蛋白酶组织抑制因子(TIMP)-1的表达,明胶酶谱法检测MMPs活性。结果ACEI组较ADR-DCM组病死率明显降低(12％和40％,P<0．01)。与对照组比较,ADR-DCM组大鼠左室内径扩大及心功能明显下降,ACEI组左室内径增加程度降低及心功能各项指标改善。ADR-DCM组MDA含量较对照组增加(P<0．01),而ACEI治疗可降低MDA含量。苦味酸天狼星红染色显示ADR-DCM组左室胶原明显增加,CVF增高;ACEI组CVF显著降低(P<0．01)。ADR-DCM组左室心肌MMP-2、MMP-9mRNA表达较对照组明显升高(P<0．01),MMPs明胶酶活性显著增加(P< 0．01),ACEI明显抑制MMP-2、MMP-9mRNA表达,降低升高的MMPs明胶酶活性,而TIMP-1的表达在3组差异无统计学意义(P>0．05)。结论阿霉素心肌病大鼠左室心肌MMPs表达及活性上调,卡托普利部分通过抑制MMPs表达及活性逆转阿霉素心肌病大鼠左室重构,改善心功能。
Objective To investigate the mechanism of angiotensin converting enzyme inhibitor Captopril in reversing left ventricular remodeling and improving cardiac function in adriamycin-induced cardiomyopathy rats. Methods Male Wistar rats were divided into 3 groups: (1) Adriamycin cardiomyopathy group (ADR-DCM group, 25 rats): Adriamycin 2.5 mg / kg and tail vein injection once a week for 10 weeks ; (2) ADR-DCM + captopril treatment group (ACEI group, 25): captopril 50 mg · kg -1 · d -1 intragastrically; (3) healthy control group only). Doxorubicin was injected two weeks after the injection of ultrasound and hemodynamic tests, thiobarbituric acid method for the detection of malondialdehyde (MDA) content, picric acid Sirius red staining of left ventricular collagen specific staining and quantitative analysis of collagen volume fraction ( CVF). The expression of MMP-2, MMP-9 and TIMP-1 were detected by RT-PCR. The activity of MMPs was detected by gelatin zymography. Results The mortality of ACEI group was significantly lower than that of ADR-DCM group (12% vs 40%, P <0.01). Compared with the control group, the left ventricular diameter and cardiac function of rats in ADR-DCM group were significantly decreased. The increased left ventricular diameter and the improvement of cardiac function in ACEI group. MDA content in ADR-DCM group was higher than that in control group (P <0.01), while ACEI treatment could reduce MDA content. The picric acid Sirius red staining showed that left ventricular collagen increased significantly and CVF increased in ADR-DCM group, but decreased in ACEI group (P <0.01). The mRNA expression of MMP-2 and MMP-9 in left ventricular myocardium in ADR-DCM group was significantly higher than that in control group (P <0.01), and MMPs activity was significantly increased (P <0.01) MMP-9mRNA expression, reduce the increased MMPs gelatinase activity, while TIMP-1 expression in the three groups, the difference was not statistically significant (P> 0.05). Conclusions The expression and activity of MMPs in left ventricular myocardium of adriamycin-induced cardiomyopathy rats were increased. Captopril partially improved left ventricular remodeling in rats with doxorubicin-induced cardiomyopathy by inhibiting MMPs expression and activity.