环磷酸腺苷应答元件结合蛋白信号转导通路对不同起搏部位致心肌电重构的影响及机制  

Role of cyclic adenosine monophosphate response element binding protein in ventricular pacing induced cardiac electrical remodeling in a canine model

作　　者：陈学思[1] 陈星星[1] 程俊华[1] 洪俊[1] 郑程[1] 赵景琳 李进[1] 林加锋[1] 

机构地区：[1]温州医科大学附属第二医院心内科,325000

出　　处：《中华心血管病杂志》2015年第4期334-340,共7页Chinese Journal of Cardiology

基　　金：国家自然科学基金（81070155）

摘　　要：目的 观察心室不同部位起搏对心肌电重构变化、环磷酸腺苷（cAMP）应答元件结合蛋白（CREB）差异性表达以及CREB相关通路的影响.方法 在DSA下建立beagle犬双心室起搏的动物模型,根据起搏部位不同,分为对照组（n=6）,左心室起搏组（n=6）,右心室起搏组（n=6）及双心室起搏组（n=6）.通过多普勒超声心动图、体表心电图、血浆B型利钠肽水平评价不同起搏部位致心肌电重构的影响.4周后处死犬,取心脏行心肌病理检查并用Western blot技术对细胞外调节蛋白激酶（ERK1/2）、P38分裂原激活的蛋白激酶（P38 MAPK）及CREB的表达进行检测.结果 4组心脏结构及血浆B型利钠肽水平差异无统计学意义（P＞0.05）.术后4周,对照组、右心室起搏组、左心室起搏组及双心室起搏组心电图Tp-Te间期分别为（60±12）、（92±11）、（91±10）、（79±13）ms,3个起搏组均长于对照组（P＜0.05）,双心室起搏组短于右心室及左心室起搏组（P＜0.05）;4组模型的心肌病理切片均未发现病理性改变;Western blot结果显示,左心室起搏组起搏侧心肌、右心室起搏组起搏侧心肌及双心室起搏组双心室心肌磷酸化ERK1/2（p-ERK1/2）表达水平分别为2.7±0.4、2.4±0.2、1.7±0.1、1.9±0.2,磷酸化P38 MAPK（p-P38 MAPK）表达水平分别为1.9±0.3、1.7±0.2、0.8±0.1,1.1±0.1,磷酸化CREB（p-CREB）表达水平分别为2.1±0.2、2.0±0.2、2.7±0.4、2.6±0.3,与左心室起搏组及右心室起搏组起搏侧心肌比较,双心室起搏组双心室心肌p-ERK1/2及p-P38 MAPK表达较低（P＜0.05）,而P-CREB表达较高（P＜0.05）.结论 通过测量心脏电重构指标Tp-Te间期,发现心室起搏可导致犬心肌的电重构,并能促进心肌ERK1/2及P38MAPK的磷酸化,抑制心肌CREB磷酸化.ERK1/2及P38 MAPK的磷酸化可能是心肌电重构作用机制之一,而CREB的磷酸化抑制心肌电重构.通过与单心室起搏组起搏组比较,双心室Objective This project is designed to explore the potential role of cyclic adenosine monophosphate （cAMP） response element binding protein （CREB） in cardiac electrical remodeling induced by pacing at different ventricular positions in dogs.Methods An animal model by implanting the pacemakers in beagles was established.According to the different pacing positions,the animals were divided into 4 groups：conditional control group （n =6）,left ventricle pacing group （n =6）,right ventricle pacing group （n =6）and bi-ventricle pacing group （n =6）.Cardiac and electrical remodeling were observed by echocardiography,electrocardiogram and plasma BNP.Myocardial pathology and protein expression of extracellular regulated protein kinases1/2 （ERK1/2）,P38 mitogen activated protein kinases （P38 MAPK） and CREB were examined at 4 weeks post pacing.Results Cardiac structure and plasma BNP level were similar among 4 groups （all P 〉 0.05）.Electrocardiogram derived Tp-Te interval was significantly prolonged post pacing （92 ± 11,91 ± 10,and 79 ± 13 ms vs.60 ± 12 ms）,and the Tp-Te interval in bi-ventricle pacing group was shorter than in left or right ventricle pacing group（P 〈 0.05）.Western blot results showed that the expression of p-ERK1/2 in left ventricular myocardium of left ventricle pacing group,right ventricular myocardium of right ventricle pacing group and bi-ventricular myocardium of bi-ventricle pacing group was 2.7 ± 0.4,2.4 ± 0.2,1.7 ± 0.1 and 1.9 ± 0.2,respectively,the expression of p-P38 MAPK was 1.9 ±0.3,1.7 ± 0.2,0.8 ±0.1 and 1.1 ± 0.1,respectively,and the expression of p-CREB was 2.1 ± 0.2,2.0 ±0.2,2.7 ± 0.4 and 2.6 ± 0.3,respectively.The p-ERK1/2 and p-P38 MAPK expression of hi-ventricle pacing group was lower,but the p-CREB expression was higher compared to the other pacing groups（P 〈 0.05）.Conclusions Ventricular pacing could induce electrical remodeling evidenced by prolonged Tp-Te interval and increased phosphorylation of ERK1/2 and p38 MAPK and

关 键 词：心脏起搏器 人工 心室重构 cAMP应答元件调节器 

分 类 号：R318.11[医药卫生—生物医学工程]