神经再生诱发心源性猝死的钾通道机制研究
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摘要
背景与目的心源性猝死(SCD)是指由各种心脏疾患导致的突然意外死亡,最常见于冠心病并发心肌梗塞(MI)患者,多由致命性心律失常——心室纤颤(VF)所致。MI慢性期发生的SCD(迟发性SCD)的发病机制目前仍未阐明。近年来有些学者报道心梗后心脏自主神经异常芽生可诱发SCD,并且左心交感神经再生可导致心电图QT间期延长。QT间期延长是室性心动过速(VT)、VF和SCD的重要危险因子,而后除极是产生触发性心律失常的重要原因。由于QT间期延长的最重要原因是心肌细胞动作电位时程(APD)延长,而APD延长反映心肌细胞复极延缓,后者的最可能原因是钾通道的表达和功能的降低;同时,触发活动多由心肌细胞静息电位不稳定所致,因此我们推测,参与心肌细胞动作电位复极的一些钾电流(如瞬时外向钾电流Ito和延迟整流钾电流IK等),以及参与心肌细胞静息电位(RP)形成的钾通道(内向整流钾电流I_(Kl))的表达和功能降低,可能是心脏自主神经再生和重塑诱发SCD的重要机制。本工作的目的是验证这些推测,并重点研究即心交感神经过度增生对Ito和I_(Kl)的表达和功能的影响,以及对心率变异性(HRV)的影响。
方法实验动物用成年雄性Wistar大鼠,体重200-250g。利用内源性NGF合成诱导剂4-甲基邻苯二酚(4-MC)慢性腹腔注射促进心交感神经芽生;用液氮经腹腔冷冻法造成局部心肌冻伤坏死以模拟心肌梗塞(MI);膜片箝技术全细胞记录分析单个心肌细胞Ito和I_(Kl)的电流密度;用Western-blot技术测定心肌细胞Kv4.2和Kir2.1(分别编码Ito和I_(Kl)通道α亚基)蛋白表达的变化,以β-actin为内参照。记录大鼠体表心电图,分析交感神经芽生和重塑对HRV的影响。实验动物共分五组(每组n=8):(1)4-MC组:观察单纯4-MC慢性给药对神经芽生对心肌细胞Ito和I_(Kl)表达和功能的影响;(2)MI组:观察单纯心梗对Ito和I_(Kl)的影响;(3)MI+4-MC组:用4-MC加强MI后心脏神经再生,观察心肌细胞Ito和I_(Kl)表达和功能的变化;(4)假手术组(正常对照组)。(5)急性4-MC组:观察4-MC本身对心肌的电生理特性是否有影响。另有18只大鼠分为三组(每组n=6)分别观察正常对照以及急、慢性4-MC给药情况下HRV的变化。
结果(1)4-MC组和MI+4-MC组的心交感神经分布密度明显高于对照组;(2)4-MC组、MI组和MI+4-MC组动物左心室心肌细胞的Ito和I_(Kl)电流密度明显低于对照组,其中以MI+4-MC组的Ito电流密度降低最为显著;(3)Ito和I_(Kl)电流的动力学特征在不同组中没有明显差异;(4)急性注射4-MC对大鼠左心室心肌细胞Ito和I_(Kl)电流密度无明显影响;(5)4-MC组、MI组和MI+4-MC组的Kv4.2和Kir2.1通道的蛋白表达水平明显低于对照组,其中以MI+4-MC组的Kv4.2和Kir2.1蛋白表达降低最为显著;(6)慢性腹腔注射4-MC造成心交感神经芽生可使大鼠心率变异性(HRV)的多个参数均明显降低,而急性4-MC给药对HRV没有明显影响。
结论4-MC慢性注射可导致心交感神经芽生、重塑和神经分布密度增高;心交感神经芽生可使心肌细胞Ito和I_(Kl)的膜蛋白水平和电流密度均降低,而且这些作用可被心梗所加强;心交感神经芽生可导致HRV降低,而急性4-MC注射对Ito和I_(Kl)电流无明显影响,对HRV也没有明显影响,提示上述4-MC的作用是通过诱导心交感神经芽生实现的,而不是4-MC的急性药理作用所致。该项研究提示,心交感神经芽生对心肌细胞Ito和I_(Kl)通道的下调作用可能是慢性心梗患者心交感神经芽生诱发心律失常及SCD的重要机制之一。
Background and Objective Sudden cardiac death(SCD) refers to sudden and unexpected death caused by various cardiac diseases,which mostly is the result of life-threatening arrhythmias such as ventricular fibrillation(VF).SCD occurs mainly among patients with coronary artery diseases,especially in those with myocardial infarction(MI).The underlying mechanism of SCD in chronic MI is poorly understood. Recently,it is reported that cardiac sympathetic nerve sprouting in chronic MI induced VT, VF and SCD.Furthermore,sympathetic nerve sprouting in left ventricle resulted in long QT syndrome(LQTS).It is well known that LQT is a critical risk factor of SCD,and is mainly caused by prolongation of action potential duration(APD),we hypothesize that down-regulation of the key potassium channels which are responsible for the repolarization of action poteltial and the mantinence of resting potential,such as transient outward potassium current(Ito) and inward rectifier potassium current(I_(K1)),is one of the leading mechanisms accounts for the induction of arrhythmias and SCD by nerve sprouting.The purpose of the present study is to test this hypothesis.
Methods Adult Wistar rats weighing 200～250g were used in this study.To induce cardiac nerve sprouting,4-methylcatechol(4-MC,10μg/kg body weight),a potent stimulator of endogenous NGF synthesis,was injected intraperitoneally daily for 4 weeks. MI was induced by liquid nitrogen freeze-thaw injury.The current densities of Ito and Ik1 was analyzed by whole cell recording technique.The protein levels of membrane Kv4.2 and Kir2.1 were evaluated by Western blotting and normalized to the level ofβ-actin. HRV perameters,such as mean RR intervals,SDNN of RR intervals,RMSSD of RR intervals,ApEn of RR intervals and Poincaréplot of RR intervals,were analysized based on the ECG recording.The animals were devided into five groups:(1) 4-MC group,served to observe the effect of nerve sprouting on the expression and function of Ito and I_(k1).(2) MI group,to observe the effect of MI on the expression and function oflto and I_(k1).(3) MI+4-MC group,to observe the effect of a combination of MI and nerve sprouting on the expression and function of Ito and I_(k1).(4) Sham surgery group(normal control group).(4) Acute 4-MC group,to observe the direct effect of 4-MC on Itol and Ik1 currents.An extra of 18 rats were devided into three groups(n=6 for each group) to observe the HRV changes at the conditions of acute 4-MC,chronic 4-MC and normal control,respectively.
Results(1) Cardiac sympathetic nerves densities significally increased in 4-MC and MI+4-MC groups compared with sham group;(2) the current densities of Ito and Ik1 of the left ventricular(LV) myocytes decreased significantly in groups of 4-MC,MI and MI+4-MC compared with control group(P＜0.01),with the lowerest values found in the MI+4-MC group;(3) there was no difference in the current dynamics of Ito and I_(k1) among these groups;(4) acute injection of 4-MC did not affect any of these potassium currents in LV myocytes;(5) the membrane protein levels of Kv4.2(αsubunit of Ito channel) and Kir2.1(αsubunit of Ik1 channel) significantly decreased in the LV myocytes from 4-MC group,MI group and MI+4-MC group compared with sham sugery group(P＜0.01),with the lowerest values found in MI+4-MC group;(5) The HRV decreased in animals treated with chronic 4-MC injection but not in animals received acute 4-MC injection,as shown by the values of mean RR intervals,SDNN,RMSSD,ApEn and Poincaréplot of RR intervals.
Conclusion Chronic 4-MC injection induces cardiac sympathetic nerve sprouting, remodeling and hyperinnervation and downregulates both the membrane protein levels and current densities of Ito and Ik1 in LV myocytes.MI facilitates the downregulation of Ito and Ik1.Cardiac sympathetic nerve sprouting also decreases HRV.Acute 4-MC did not affect the current density and HRV,suggesting that the decreases in both the expression and function of Ito and Ik1 channels and HRV are related with nerve sprouting but not with the acute pharmacological effect of 4-MC.These results suggest that downregulation of Ito and Ik1 may be one of the leading mechanisms by which cardiac nerve sprouting induces ventricular arrhythmias ans SCD in chronic MI.
方法实验动物用成年雄性Wistar大鼠,体重200-250g。利用内源性NGF合成诱导剂4-甲基邻苯二酚(4-MC)慢性腹腔注射促进心交感神经芽生;用液氮经腹腔冷冻法造成局部心肌冻伤坏死以模拟心肌梗塞(MI);膜片箝技术全细胞记录分析单个心肌细胞Ito和I_(Kl)的电流密度;用Western-blot技术测定心肌细胞Kv4.2和Kir2.1(分别编码Ito和I_(Kl)通道α亚基)蛋白表达的变化,以β-actin为内参照。记录大鼠体表心电图,分析交感神经芽生和重塑对HRV的影响。实验动物共分五组(每组n=8):(1)4-MC组:观察单纯4-MC慢性给药对神经芽生对心肌细胞Ito和I_(Kl)表达和功能的影响;(2)MI组:观察单纯心梗对Ito和I_(Kl)的影响;(3)MI+4-MC组:用4-MC加强MI后心脏神经再生,观察心肌细胞Ito和I_(Kl)表达和功能的变化;(4)假手术组(正常对照组)。(5)急性4-MC组:观察4-MC本身对心肌的电生理特性是否有影响。另有18只大鼠分为三组(每组n=6)分别观察正常对照以及急、慢性4-MC给药情况下HRV的变化。
结果(1)4-MC组和MI+4-MC组的心交感神经分布密度明显高于对照组;(2)4-MC组、MI组和MI+4-MC组动物左心室心肌细胞的Ito和I_(Kl)电流密度明显低于对照组,其中以MI+4-MC组的Ito电流密度降低最为显著;(3)Ito和I_(Kl)电流的动力学特征在不同组中没有明显差异;(4)急性注射4-MC对大鼠左心室心肌细胞Ito和I_(Kl)电流密度无明显影响;(5)4-MC组、MI组和MI+4-MC组的Kv4.2和Kir2.1通道的蛋白表达水平明显低于对照组,其中以MI+4-MC组的Kv4.2和Kir2.1蛋白表达降低最为显著;(6)慢性腹腔注射4-MC造成心交感神经芽生可使大鼠心率变异性(HRV)的多个参数均明显降低,而急性4-MC给药对HRV没有明显影响。
结论4-MC慢性注射可导致心交感神经芽生、重塑和神经分布密度增高;心交感神经芽生可使心肌细胞Ito和I_(Kl)的膜蛋白水平和电流密度均降低,而且这些作用可被心梗所加强;心交感神经芽生可导致HRV降低,而急性4-MC注射对Ito和I_(Kl)电流无明显影响,对HRV也没有明显影响,提示上述4-MC的作用是通过诱导心交感神经芽生实现的,而不是4-MC的急性药理作用所致。该项研究提示,心交感神经芽生对心肌细胞Ito和I_(Kl)通道的下调作用可能是慢性心梗患者心交感神经芽生诱发心律失常及SCD的重要机制之一。
Background and Objective Sudden cardiac death(SCD) refers to sudden and unexpected death caused by various cardiac diseases,which mostly is the result of life-threatening arrhythmias such as ventricular fibrillation(VF).SCD occurs mainly among patients with coronary artery diseases,especially in those with myocardial infarction(MI).The underlying mechanism of SCD in chronic MI is poorly understood. Recently,it is reported that cardiac sympathetic nerve sprouting in chronic MI induced VT, VF and SCD.Furthermore,sympathetic nerve sprouting in left ventricle resulted in long QT syndrome(LQTS).It is well known that LQT is a critical risk factor of SCD,and is mainly caused by prolongation of action potential duration(APD),we hypothesize that down-regulation of the key potassium channels which are responsible for the repolarization of action poteltial and the mantinence of resting potential,such as transient outward potassium current(Ito) and inward rectifier potassium current(I_(K1)),is one of the leading mechanisms accounts for the induction of arrhythmias and SCD by nerve sprouting.The purpose of the present study is to test this hypothesis.
Methods Adult Wistar rats weighing 200～250g were used in this study.To induce cardiac nerve sprouting,4-methylcatechol(4-MC,10μg/kg body weight),a potent stimulator of endogenous NGF synthesis,was injected intraperitoneally daily for 4 weeks. MI was induced by liquid nitrogen freeze-thaw injury.The current densities of Ito and Ik1 was analyzed by whole cell recording technique.The protein levels of membrane Kv4.2 and Kir2.1 were evaluated by Western blotting and normalized to the level ofβ-actin. HRV perameters,such as mean RR intervals,SDNN of RR intervals,RMSSD of RR intervals,ApEn of RR intervals and Poincaréplot of RR intervals,were analysized based on the ECG recording.The animals were devided into five groups:(1) 4-MC group,served to observe the effect of nerve sprouting on the expression and function of Ito and I_(k1).(2) MI group,to observe the effect of MI on the expression and function oflto and I_(k1).(3) MI+4-MC group,to observe the effect of a combination of MI and nerve sprouting on the expression and function of Ito and I_(k1).(4) Sham surgery group(normal control group).(4) Acute 4-MC group,to observe the direct effect of 4-MC on Itol and Ik1 currents.An extra of 18 rats were devided into three groups(n=6 for each group) to observe the HRV changes at the conditions of acute 4-MC,chronic 4-MC and normal control,respectively.
Results(1) Cardiac sympathetic nerves densities significally increased in 4-MC and MI+4-MC groups compared with sham group;(2) the current densities of Ito and Ik1 of the left ventricular(LV) myocytes decreased significantly in groups of 4-MC,MI and MI+4-MC compared with control group(P＜0.01),with the lowerest values found in the MI+4-MC group;(3) there was no difference in the current dynamics of Ito and I_(k1) among these groups;(4) acute injection of 4-MC did not affect any of these potassium currents in LV myocytes;(5) the membrane protein levels of Kv4.2(αsubunit of Ito channel) and Kir2.1(αsubunit of Ik1 channel) significantly decreased in the LV myocytes from 4-MC group,MI group and MI+4-MC group compared with sham sugery group(P＜0.01),with the lowerest values found in MI+4-MC group;(5) The HRV decreased in animals treated with chronic 4-MC injection but not in animals received acute 4-MC injection,as shown by the values of mean RR intervals,SDNN,RMSSD,ApEn and Poincaréplot of RR intervals.
Conclusion Chronic 4-MC injection induces cardiac sympathetic nerve sprouting, remodeling and hyperinnervation and downregulates both the membrane protein levels and current densities of Ito and Ik1 in LV myocytes.MI facilitates the downregulation of Ito and Ik1.Cardiac sympathetic nerve sprouting also decreases HRV.Acute 4-MC did not affect the current density and HRV,suggesting that the decreases in both the expression and function of Ito and Ik1 channels and HRV are related with nerve sprouting but not with the acute pharmacological effect of 4-MC.These results suggest that downregulation of Ito and Ik1 may be one of the leading mechanisms by which cardiac nerve sprouting induces ventricular arrhythmias ans SCD in chronic MI.
引文
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