丹参酮ⅡA对腹主动脉缩窄大鼠肥厚心肌血管紧张素Ⅱ受体及PKC/MAPK信号通路的影响

Effect of Tanshinone ⅡA on Angiotensin Ⅱ Receptor and PKC/MAPK Signal Pathway in Hypertrophic Myocardium Rats Induced by Abdominal Aorta Coarctation

目的:研究丹参酮(Tanshinone,TSN)ⅡA对缩窄腹主动脉大鼠肥厚心肌的作用和机制。方法:采用腹主动脉缩窄(abdominal aortic constriction,AAC)法制备大鼠左室肥厚模型,造模次日大鼠随机分为模型对照组、丹参酮ⅡA 5、10、20 mg/kg组、缬沙坦10 mg/kg组,另设假手术对照组,每组分别给予同体积相应药物或纯净水,1次/d,连续4 w。检测大鼠左心室结构与功能、血流动力学指标,计算左心室质量指数;观察大鼠心肌病理形态改变;ELISA法测定大鼠心肌组织中血管紧张素Ⅱ(AngⅡ)及内皮素-1(ET-1)含量;检测β-肌球蛋白重链(β-MHC)和心房利钠因子(ANF)的含量;观察心肌组织中蛋白激酶C(PKC)和丝裂原活化蛋白激酶(MAPK)信号蛋白及mRNA表达。结果:与正常对照组比较,模型对照组大鼠血压和左室内压均明显升高(P<0.05),左心室壁明显增厚,左室内径明显缩小,心搏量明显减少(P<0.05);左室质量指数及左右心室质量分数显著增加(P<0.05);心肌细胞直径明显增大,心肌血管周围存在大量胶原纤维沉积,心肌组织中AngⅡ及ET-1含量明显升高(P<0.05);心肌肥厚标志物β-MHC、ANF含量及PKC-β、Raf-1、p-ERK 1/2表达明显增加,而MKP-1表达明显降低(P<0.05);与模型对照组比较,丹参酮ⅡA 10、20 mg/kg组及缬沙坦10 mg/kg组均能使大鼠左心功能及室壁厚度明显改善,心室内径及心博量明显增加(P<0.05);左室质量指数及心肌细胞直径明显改善,使心肌纤维排列趋于整齐,心肌组织中胶原纤维沉积及AngⅡ、ET-1含量明显降低(P<0.05);使心肌肥厚标志物ANF、β-MHC及PKC-β、Raf-1、p-ERK 1/2表达明显降低,而MKP-1表达明显升高(P<0.05)。结论:丹参酮ⅡA抗心肌肥厚的作用可能与其降低AngⅡ的含量、阻滞PKC/MAPK信号传导通路有关,该作用是非血压依从性的。

Objective:To study the effect of Tanshinone(TSN)ⅡA on abdominal aorta constriction(AAC)-induced hypertrophic myocardium in rats and the mechanism.Methods:AAC was used to induce left ventricular hypertrophy in rats.Rats were randomized into the normal group,model group,5,10,and 20 mg/kg TSNⅡA groups,and 10 mg/kg valsartan group.Then the same volume of corresponding drug or purified water was given(once a day,4 weeks).The structure,function,and hemodynamic indexes of rat left ventricle were detected,and the weight index was calculated.Moreover,the pathological changes of rat myocardium were observed and the content of angiotensinⅡ(AngⅡ)and endothelin-1(ET-1)in rat myocardium was determined by ELISA.The levels ofβ-myosin heavy chain(β-MHC)and atrial natriuretic factor(ANF)were detected and the protein and mRNA expression of protein kinase C(PKC)and mitogen-activated protein kinase(MAPK)in myocardial tissue were measured.Results:Compared with the normal group,the model group demonstrated increase in blood pressure and left ventricular pressure(P<0.05),thickening of left ventricular wall,decrease in left ventricular diameter and stroke volume(P<0.05),rise of weight index of ventricle and the weight ratio of the left and right ventricles(P<0.05),elevation of the diameter of myocardial cells,accumulation of collagen fibers around myocardial blood vessels,rise of the content of AngⅡand ET-1 in myocardial tissue(P<0.05),up-regulation of cardiac hypertrophy markersβ-MHC,ANF,PKC-β,Raf-1,and p-ERK 1/2,and down-regulation of MKP-1(P<0.05).The hemodynamic indexes of the TSNⅡA groups were not significantly different from those of the model group(P>0.05).However,10 and 20 mg/kg TSNⅡA and 10 mg/kg valsartan improved the left ventricular function and ventricular wall thickness of rat,increased the ventricular diameter,improved stroke volume(P<0.05),and significantly increased left ventricular weight index and the diameter of myocardial cells,so that the arrangement of myocardial fibers tended to be more orderly.Moreover,10 and 20 mg/kg TSNⅡA and 10 mg/kg valsartan decreased the deposition of collagen fibers in myocardial tissues and the content of AngⅡand ET-1(P<0.05),down-regulated levels of cardiac hypertrophy markers ANF,β-MHC,PKC-β,Raf-1,and p-ERK 1/2,and up-regulated the level of MKP-1(P<0.05).Conclusion:The effect of TSNⅡA on myocardial hypertrophy may be related to its down-regulation of AngⅡcontent and blocking the PKC/MAPK signal pathway.This effect is non-blood pressure compliance.