MAPK信号途径在一氧化氮抑制大鼠心肌肥大中的作用

Role of mitogen activated protein kinase in the inhibition of myocardial hypertrophy by nitric oxide in renovascular hypertensive rats

实验观察了一氧化氮 (NO)前体L 精氨酸对肾性高血压大鼠心肌组织eNOS蛋白表达及亚硝酸盐 /硝酸盐含量、MKP 1蛋白表达及MAPK活性的影响 ,以及与心肌肥厚的关系。采用两肾一夹Goldblatt肾性高血压模型 ,随机分为 5组 :L 精氨酸高、中、低剂量组 ,分别于术后第 5周给予L 精氨酸 5 0、15 0及 45 0mg/kg;L NAME组 ,腹腔注射L NAME 10mg/kg,同时给予L 精氨酸 15 0mg/kg ;高血压对照组 ,正常饮水 ,以及另设的一假手术对照组。用药 8周后 ,用插管法测量大鼠动脉血压、左心室重与体重比值 ,用胶内原位磷酸化法测MAPK活性、免疫印迹法检测心肌组织eNOS及MKP 1蛋白表达、酶还原法测定心肌组织亚硝酸盐 /硝酸盐含量。结果表明 :(1)L 精氨酸可明显抑制肾动脉狭窄术后的血压升高、左心室重与体重比增加 ,增加心肌组织eNOS、MKP 1蛋白表达及亚硝酸盐 /硝酸盐含量 ,降低心肌组织MAPK活性 ,其中以 15 0mg/kg组作用最为明显 ;(2 )NOS抑制剂L NAME可明显抑制L 精氨酸的以上作用。肾性高血压大鼠心肌组织eNOS蛋白表达下降。NO生成减少及MKP 1蛋白表达下降以及MAPK活性增强可能与高血压及心肌肥厚形成有关 ,L 精氨酸通过促进心肌组织eNOS蛋白表达、增加NO产生和MKP 1表达。

The aim of this study was to examine the effects of L arginine, a nitric oxide (NO) precursor, on protein expression of endothelial nitric oxide (eNOS), nitrite/nitrate content, protein expression of mitogen activated protein kinase phosphatase 1 (MKP 1) and the activity of mitogen activated protein kinase (MAPK) in cardiac tissues in renovascular hypertensive rats (RHR). The Goldblatt renovascular hypertensive model was established by two kidney one clip method. The rats were divided into four groups, respectively treated with 50, 150 and 450 mg/kg L arginine and 150 mg/kg L arginine plus 10 mg/kg L NAME (an eNOS inhibitor) (ip). Another group did not receive specific treatment from the 5th week after renal artery constriction. Control group was sham operated. Mean arterial blood pressure (MABP) and the ratio of left ventricular weight to body weight (LVW/BW) were measured 8 weeks after treatment. eNOS protein expression, nitrite/nitrate content, MKP 1 protein expression and MAPK activity in cardiac tissues were detected using Western blot analysis, enzyme reduction method and substrate in gel kinase assay, respectively. It was found that L arginine significantly inhibited the increase of MABP and LVW/BW, attenuated the activity of MAPK, increased protein expression of eNOS and MKP 1 and potentiated production of NO in cardiac tissue with the most effective dosage of 150 mg/kg, and these effects of L arginine could be inhibited by L NAME. These results suggest that MKP 1 may play an important role in the NO induced inhibition of myocardial hypertrophy. The anti hypertrophic effects of L arginine may involve increase of eNOS protein expression and NO production, poten tiation of MKP 1 protein expression, and inhibition of MAPK activity in the cardiac tissue of RHR.