外源性H_2S对糖尿病大鼠心肌纤维化及MMP-13、MMP-14和TIMP-1表达的影响

Effect of exogenous hydrogen sulfide on myocardial fibrosis and MMP-13,MMP-14 and TIMP-1 expression in myocardial tissues of diabetic rats

目的:探讨外源性H2S对糖尿病大鼠心肌纤维化及基质金属蛋白酶-13(matrix metalloproteinase-13,MMP-13)、MMP-14和金属蛋白酶组织抑制因子-1(tissue inhibitor of metallo proteinase-1,TIMP-1)表达的影响。方法:52只SD雄性大鼠随机分成4组(每组13只):正常对照组、糖尿病大鼠组(STZ组)、硫化氢干预糖尿病大鼠组(STZ+H2S组)、硫化氢干预正常大鼠组(H2S组)。腹腔注射链脲佐菌素(streptozotocin,STZ)(40 mg/kg)建立糖尿病模型;正常对照组每天腹腔注射等剂量生理盐水;STZ组与H2S组每天腹腔注射硫氢化钠(H2S供体)溶液(100μmol/kg)。HE和VG染色观察心肌纤维化,Western blot检测Ⅲ型胶原蛋白以及MMP-13、MMP-14和TIMP-1的表达。结果:排除死亡后每组成功建模量分别为12、9、9、10只;与正常对照组相比,STZ组心肌细胞排列紊乱,细胞间胶原纤维堆积明显增加,Ⅲ型胶原蛋白表达明显上调(P<0.01),而MMP-13、MMP-14和TIMP-1蛋白表达也增加(P<0.01);与STZ组相比,STZ+H2S组大鼠心肌细胞排列紊乱有所改善,细胞间胶原纤维堆积减少,Ⅲ型胶原蛋白表达下调(P<0.01),MMP-13、MMP-14和TIMP-1蛋白的表达也明显减少(P<0.01)。结论:H2S可改善糖尿病大鼠心肌纤维化,其机制可能与下调MMP-13、MMP-14和TIMP-1蛋白的表达有关。

Objective：To investigate the effects of exogenous hydrogen sulfide on the expression of type Ⅲ collagen,tissue inhibitor of metallo proteinase-1（TIMP-1）,matrix metalloproteinase-13（MMP-13） and MMP-14 protein and myocardial fibrosis. Methods：Totally 52 male SD rats were randomly divided into four groups（n=13） ：control group,diabetes rats group（STZ group）,diabetes rats treated with H2 S group（STZ ＋H2S group）,normal rats treated with H2 S group（H2S group）. Diabetic rats were induced by intraperitoneal injection of streptozotocin（STZ,40 mg/kg）. Rats in control group were only given intraperitoneal injection with equal amount of normal saline（NS）. STZ group and H2 S group were injected with Na HS（the provider of H2 S,100 μmol/kg） solution. The pathological morphological changes in myocardial fiber were analyzed by HE staining and VG staining;the expressions of type Ⅲ collagen,TIMP-1,MMP-13 and MMP-14 were analyzed by Western blot. Results：The number of rats in each group after successful modeling was 12,9,9 and 10,respectively. Compared with those of control group,collagen deposition and myocardial fibrosis increased obviously,the expressions of type Ⅲ collagen,MMP-13,MMP-14 and TIMP-1 were significantly increased（P0.01） in STZ group,which were dramatically reversed by H2 S treatment（P0.01）. Conclusion：H2S could reduce myocardial fibrosis in diabetic rats,which may be related to the inhibition of MMP-13,MMP-14 and TIMP-1expression.