糖尿病大鼠不同阶段心肌内MMP-9与TIMP-1表达及全反式维甲酸的干预作用

Expression of MMP-9 and TIMP-1 in myocardium of the diabetic rats and the therapeutic effects of all-trans retinoic acid

目的动态观察糖尿病(DM)大鼠心肌组织内基质金属蛋白酶-9(MMP-9)与组织金属蛋白酶抑制物-1(TIMP-1)表达水平的变化及全反式维甲酸(ATRA)对两者的干预作用。方法链脲菌素(STZ)法复制SD大鼠DM模型,将造模成功的大鼠随机分为DM30d组、DM60d组、DM+ATRA处理30d组和DM+ATRA处理60d组。另取同期大鼠作为正常对照,分设对照30d组、对照60d组、对照+AT-RA30d组和对照+ATRA60d组。各组大鼠30d和60d测量心质量/体质量比值,HE染色观察心肌结构的改变,并用免疫组化技术检测心肌组织中MMP-9与TIMP-1表达水平。结果各DM组大鼠心质量、体质量均较各对照组低,而心质量/体质量比值明显升高(均P<0.05),而DM+ATRA组与DM组比较,上述指标明显改善(P<0.05);各DM组大鼠空腹血糖较对照组升高(P<0.05),而DM+ATRA组与DM组比较,差异无统计学意义;各DM组大鼠心肌组织中MMP-9与TIMP-1表达水平均较同期各对照组明显升高(P<0.05),而DM+ATRA组较DM组降低(P<0.05)。光镜下可见DM组心肌结构改变明显,而DM+ATRA组病变减轻。结论高糖状态下,大鼠心肌内MMP-9与TMIP-1表达水平失衡可能是导致大鼠心脏肥大和组织形态改变的原因,ATRA可能通过使心肌内MMP-9与TIMP-1表达恢复平衡而改善心肌重构。

Objective To observe the expression of metalloproteinases-9 （MMP-9） and tissue inhibitors of metalloproteinases-1 （TIMP-1） in myocardium of diabetic rat dynamically, and the therapeutic effect of all-tram retinoic acid （ATRA）.Methods Diabetic rat models were induced with streptozotocin （SIZ,60 mg/kg body weight intravenously） and divided into DM 30 d, DM 60 d, DM ＋ ATRA 30 d and DM ＋ ATRA 60 d groups randomly. There were normal rats as control group. The ratio of heart mass and body mass of rats were measured, and the myocardium histomorphology with Haematoxylin and Eosin（HE） staining were observed. And the expressions of MMP-9 and TIMP- 1 were estimated with immunohistocbemical technique. Results The level of heart mass and body mass were lower in DM group than normal control group, otherwise the ratio of heart mass and body mass was increased （ P 〈 0.05）. The fasting blood glucose was significant increased in the diabetic rat （ P 〈 0.05） and there was no statistical significant between ATRA treatment group and DM group. It demonstrated that the expression of MMP-9 and TIMP-1 in diabetic rats was higher than the same period control group （ P 〈 0.05）, and DM ＋ ATRA group was lower than DM group （ P 〈 0.05）. The myocardium histomorphology was significantly changed in the DM group, although ATRA treatment lessen the change. Conclusion The unbalance of the expression of MMP-9 and TIMP-1 may induce myocardium hypertrophy and chance of histomorphology in diabetic rats, the ATRA could be used to improve the myocardium reconstruction through recovery the unbalance.