基质金属蛋白酶在心肌肥厚大鼠细胞外基质重塑中的作用及氯沙坦干预

Role of metalloproteinases in rat cardiac extracellular matrix remodeling and effects of losartan on it

目的 :探讨基质金属蛋白酶 (MMP 9)及其生理性抑制剂TIMP 1和转化生长因子β1(TGF β1)在心肌肥厚大鼠细胞外基质重塑中的作用及氯沙坦干预的效果 .方法 :雄性SD大鼠随机分为 3组 :①对照组 ;②去甲肾上腺素 (nore pinephrine,NE)组 (1.0 6mg·kg-1·d-1× 15d) ;③NE +氯沙坦组 (10mg·kg-1·d-1× 15d) .NE腹腔注射 ,2次·d-1,连续15d ,建立心肌肥厚的模型 .应用超声心动图及病理学方法评价整体心肌肥厚和组织胶原的表达 .用逆转录 聚合酶链反应法 (RT PCR)及免疫组化方法检测MMP 9,TIMP 1和TGF β1mRNA和蛋白表达情况 .结果 :大鼠腹腔注射NE后发生左心室肥厚及纤维化 ,胶原的含量及MMP 9,TIMP 1和TGF β1的蛋白、mRNA的表达显著高于健康对照组 (P <0 .0 1) .氯沙坦能降低室间隔的厚度 ,减少左室心肌中总体胶原、I型、III型胶原的合成及MMP 9,TGF β1的表达 (P <0 .0 1) .结论 :MMP 9,TIMP 1和TGF β1与NE诱导的心肌细胞外基质重塑有关 .氯沙坦能有效的防治心肌肥厚及细胞外基质重塑 ,这一效应与其降低心肌中高表达的MMP 9和TGF β1有关 .

AIM: To investigate the role of metalloproteinase (MMP 9), tissue inhibitor of metalloproteinase (TIMP 1) and transforming growth factorβ1 (TGF β1) in cardiac hypertrophy and extracellular matrix remodeling and the effects of Losartan on it in a rat model. METHODS: Male SD rats were randomly divided into three groups: control group, norepinephrine group (1.06 mg·kg -1 ·d -1 ×15 d) and norepinephrine + Losartan group (10 mg·kg -1 · d -1 × 15 d). The rat cardiac hypertrophy models were established by intraperitoneal injection of norepinephrine (NE) twice a day for 15 days. Cardiac hypertrophy and extracellular matrix remodeling were evaluated by echocardiography and morphological examination. The mRNA and protein expression of matrix metalloproteinase (MMP 9), tissue inhibitor of metalloproteinase (TIMP 1) and transforming growth factorβ1 (TGF β1) was examined by reverse transcription polymerase chain reaction (RT PCR) and immunohistochemical analysis. RESULTS: NE induced hypertrophy and extracellular matrix remodeling predominantly occurred in the left ventricular and the mRNA and protein expression of the MMP 9, TIMP 1 and TGF β1 elevated ( P <0.01). After Losartan treatment, the interventricular septal thickness, total collagen, type I, type III collagen and the expression of MMP 9 and TGF β1 decreased ( P <0.01). CONCLUSION: MMP 9, TIMP 1 and TGF β1 are involved in the cardiac extracellular matrix remodeling induced by NE. Losartan can prevent the cardiac hypertrophy and extracellular matrix remodeling, which is associated with the attenuation of myocardial MMP 9 and TGF β1.