强力霉素逆转阿霉素心肌病大鼠左室重构改善心功能

目的: 研究基质金属蛋白酶(MMPs)抑制剂强力霉素(doxycycline, DOX)能否逆转阿霉素心肌病(ADR DCM)左室重构以改善心功能。方法:雄性Wistar大鼠分3组:①阿霉素心肌病组(ADR DCM, n=25),阿霉素2.5 mg·kg-1,尾静脉注射,每周1次,连续10周;②阿霉素心肌病+强力霉素治疗组(DOX, n=25), DOX30 mg·kg-1,每天1次,灌胃治疗;③正常对照组(CON,n=10)。12 周时进行超声和血流动力学检测,明胶酶谱法检测MMPs活性。结果: DOX组较 ADR DCM组死亡率明显降低(16%比 40%,P<0.01),CON组无一例死亡。与CON组相比,ADR DCM组大鼠左室舒张末期内径及收缩末期内径增加,左室短轴缩短率、左室内压最大上升速率和最大下降速率明显降低(P均<0.01)。DOX组左室内径增加程度降低,心功能各项指标改善。明胶酶谱法显示MMPs明胶酶活性显著增加(P<0.01),DOX组明显降低升高的MMPs明胶酶活性。结论:MMPs抑制剂强力霉素通过抑制MMPs活性可部分逆转ADR DCM左室重构,改善心功能。

Doxycycline, A Nonspecific Matrix Metalloproteinase Inhibitor, Attenuates Left Ventricular Remodeling and Failure in the Rat Model of Adriamycin-induced Dilated Cardiomyopathy

Objective: To determine whether the nonspecific matrix metalloproteinase (MMP) inhibitor doxycycline(DOX) could prevent adriamycin-induced dilated cardiomyopathy (ADR-DCM). Methods: Weight-matched adult male Wistar rats were randomly divided into 3 groups as follows: ① the ADR group, in which 2.5 mg·kg -1 of ADR was weekly injected via the tail veins for 10 weeks (n = 25); ② concomitant MMPs inhibition and ADR group, in which DOX as a MMPs inhibitor was administered by daily gavage at a dose of 30 mg·kg -1 ·d -1 ; and ③ the control group (n = 10). Hemodynamics and echocardiographic measurements were obtained 12 weeks after treatment. Finally, left ventricular(LV) samples were collected. MMP-2 and -9 gelatinolytic activities were measured by gelatin zymography. Results: Mortality was significantly lower in DOX-treated rats than in ADR rats (16% versus 40%, P<0.01). LV cavity dilatation was significantly attenuated in ADR-induced dilated cardiomyopathy rats given doxycycline. Doxycycline could partially normalized FS, EF and ±dp/dtmax indices of LV function, which were significantly reduced in ADR rats(P<0.01). LV myocardial MMP-2 and -9 gelatinolytic activities were increased significantly in ADR rats (both P<0.01)and were attenuated by doxycycline treatment(both P<0.01). Conclusion: Pretreatment with the MMPs inhibitor doxycycline can attenuate left ventricular remodeling and failure in a rat model of adriamycin-induced dilated cardiomyopathy by downregulating LV myocardial MMPs activities.