血管紧张素Ⅱ介导的心肌细胞肥大反应中磷酸化MAPK的作用

The Regulation of MKP-1 in Cardiomyocyte Hypertrophic Response Induced by Angiotensin Ⅱ

【目的】本研究主要是从丝裂原活化蛋白激酶 (MAPK)激活及失活角度研究该信号途径在血管紧张素Ⅱ (an giotensinⅡ ,AngⅡ )介导的心肌细胞肥大反应中作用。【方法】实验分别以 :①心肌细胞蛋白合成速率作为心肌肥大反应指标 ;②磷酸化MAPK蛋白 (p44MAPK、p42MAPK)表达反映MAPK活性状态。【结果】①AngⅡ (0 .1μmol/L)处理心肌细胞 48h ,可使3H 亮氨酸掺入明显增加 ,该作用可被CV11974明显抑制 (抑制 85 % ) ,而PD0 980 5 9可部分抑制该反应 (抑制 32 5 % ) ;②AngⅡ (0 .1μmol/L)处理心肌细胞 5min ,磷酸化MAPK蛋白表达即开始增加 ,30min左右达到高峰 ,2h基本恢复正常 ,血管紧张素Ⅱ的Ⅰ型受体 (AT1)拮抗剂CV11974(0 .1mmol/L)或MAPK激酶 (MEK)特异性抑制剂PD0 980 5 9(5 0 μmol/L)可明显抑制AngⅡ介导的磷酸化MAPK蛋白表达 (30min时分别下降 89%及 81% )。【结论】AngⅡ主要通过AT1受体激活MAPK及介导心肌肥大反应 ,抑制MAPK的激活可减轻AngⅡ介导的心肌肥大反应。MAPK通路激活是AngⅡ介导的心肌肥大反应重要机制。

Objective The study was to examine the MAPK activity and protein expression in the cardiomyocyte hypertrophic response induced by angiotensin Ⅱ(AngⅡ). Method (1) Neonatal rat cardiomyocyte hypertrophic response was assayed by protein synthesis rate. (2) Protein expression of Phosphorlated MAPK and MKP-1 were detected by Western blotting. Result (1) AngⅡ induced promotion of 3H-leucine incorporation in dose-dependent manner. Pretreatment with CV11974, a selective AT 1 receptor antagonist, or PD098059, a specific MEK inhibitor, cardiomyocyte hypertrophic response induced by AngⅡ could be inhibited by 85% and 32 5%, respectively.(2) Pretreatment of cardio myocyte with AngⅡ for 5 min, p44MAPK and p42MAPK protein expression began to increase,the peak effect was at 30 min and last for 2 h; while pretreatment with CV11974(0.1 mmol/L) or PD098059 (50 μmol/L), AngⅡ-induced increase in (p44+ p42)MAPK were inhibited by 89% and 81%, respectively. Conclusion The results suggest that activation of MAPK may play an important role in AngⅡ-induce hypertrophic response in neonatal rat cardiomyocyte, and other signal pathway may also participated in AngⅡ-induced cardiomyocyte hypertrophic response.