论文部分内容阅读
目的研究基质金属蛋白酶(MMPs)抑制剂多西环素(doxycycline,DOX)能否防治阿霉素心肌病(ADRDCM)左室重构及其作用机制。方法♂Wistar大鼠分3组:①阿霉素心肌病组(ADRDCM,n=25),阿霉素2.5mg·kg-1,尾静脉注射,每周1次,连续10wk;②阿霉素心肌病+多西环素治疗组(DOX,n=25),DOX30mg·kg-1,每天1次,灌胃治疗;③正常对照组(CON,n=10)。12wk时进行超声和血流动力学检测评价心功能,硫代巴比妥酸法检测丙二醛(MDA)含量,逆转录聚合酶链反应检测MMP2、MMP9及TIMP1的表达,明胶酶谱法检测MMPs活性。结果DOX组较ADRDCM组死亡率明显降低(16%vs40%,P<0.01)。与CON组相比,ADRDCM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。ADRDCM组MDA含量较CON组增加(P<0.01),而DOX治疗对MDA含量的增加无影响。ADRDCM组左室心肌MMP2、MMP9mRNA表达较CON组明显升高(P<0.01),MMPs明胶酶活性增加(P<0.01),DOX组明显抑制MMP2、MMP9mRNA表达,明显降低升高的MMPs明胶酶活性,而TIMP1的表达在3组间差异均无显著性(P>0.05)。结论ADRDCM左室心肌MMPs表达及活性上调,MMPs抑制剂多西环素通过抑制MMPs表达及活性可部分逆转ADRDCM左室重构,改善心功能。
Objective To investigate whether matrix metalloproteinases (MMPs) inhibitor doxycycline (DOX) can prevent left ventricular remodeling and its mechanism of action in adriamycin cardiomyopathy (ADRDCM). Methods ♂ Wistar rats were divided into three groups: ① adriamycin cardiomyopathy group (ADRDCM, n = 25), adriamycin 2.5mg · kg-1, tail vein injection once a week for 10 weeks; ② doxorubicin Cardiomyopathy + doxycycline treatment group (DOX, n = 25), DOX30mg · kg-1, once daily, intragastrically; ③control group (CON, n = 10). The cardiac function was evaluated by sonography and hemodynamics at 12 weeks. The content of malondialdehyde (MDA) was detected by thiobarbituric acid method. The expressions of MMP2, MMP9 and TIMP1 were detected by reverse transcription polymerase chain reaction. Gelatin zymography MMPs activity. Results The mortality of DOX group was significantly lower than that of ADRDCM group (16% vs 40%, P <0.01). Compared with CON group, left ventricular end-diastolic diameter and end-systolic diameter of ADRDCM group were significantly increased, shortening rate of left ventricular short axis, maximum rate of left ventricular pressure rising and maximum rate of descending were significantly decreased (all P <0.01). DOX group decreased left ventricular diameter, cardiac function improved. MDA content in ADRDCM group was higher than that in CON group (P <0.01), while DOX treatment had no effect on MDA content. The mRNA expression of MMP2 and MMP9 in left ventricular myocardium of ADRDCM group was significantly higher than that of CON group (P <0.01), and the activity of MMPs gelatinase was increased (P <0.01). DOX group significantly inhibited the expression of MMP2 and MMP9 mRNA and significantly decreased the activity of MMPs , While the expression of TIMP1 in the three groups showed no significant difference (P> 0.05). Conclusions The expression and activity of MMPs in left ventricular myocardium of ADRDCM are upregulated. Doxycycline, an inhibitor of MMPs, can partially reverse the left ventricular remodeling of ADRDCM and improve cardiac function by inhibiting the expression and activity of MMPs.