复极储备相关钾通道在心力衰竭时的变化及相互作用研究
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摘要
背景与目的：心力衰竭(心衰)时恶性室性心律失常和心源性猝死发生率增加,严重影响患者的生活质量甚至危及生命。研究显示心衰时心律失常发生率增加与复极储备障碍或功能丧失关系密切,复极储备主要依赖于快速延迟整流钾电流(IKr)通道和缓慢延迟整流钾电流(IKs)通道离子流在心肌复极过程中相互作用产生的代偿性补充,从而缓冲动作电位时程(APD)过度延长。本课题一方面利用兔腹主动脉缩窄心衰模型,研究心衰时心室肌细胞中KCNH2和KCNQ1基因在mRNA水平表达的变化情况,以及与动作电位(AP)、IKr通道和IKs通道离子流之间的关系,探讨心衰时复极储备改变的特征及机制；另一方面利用转染技术将KCNH2和KCNQ1基因导入细胞,研究二者在mRNA.蛋白及离子通道水平的相互影响,进一步探讨复极储备中离子通道间的相互作用机制。为心衰时恶性室性心律失常及心源性猝死的机制研究提供实验与理论依据。
研究方法：24只日本大耳白兔随机分为假手术组(Sham)和心衰模型组(HF),每组12只,分别行腹主动脉分离术和腹主动脉缩窄术,术后常规饲养12周,评价一般情况及心脏超声指标,判定HF组模型建立达标情况。Sham组与HF组动物均麻醉取心脏,灌流分离心室肌细胞,提取总RNA用RT-qPCR方法,比较目的基因KCNH2及KCNQ1的mRNA表达量在两组间的差别,应用膜片钳技术辅以钾离子通道阻滞剂多非利特(Dof)和293B药物,检测心衰时心室肌细胞AP,比较复极至50%的动作电位时程(APD50)、复极至90%的动作电位时程(APD90)、动作电位幅值(APA)和静息膜电位(RMP)在各条件下的变化情况,测定心室肌细胞IKr电流和IKs电流在不同条件下的改变。另一方面应用瞬时转染技术,将HEK293细胞随机分为7组,即单独将KCNQ1(Q1组)、野生型WT-KCNH2(WT组)、功能获得型T618I-KCNH2(T618I组)和功能缺失型V535M-KCNH2(V535M组)与空质粒共转染,及将KCNQ1分别与各功能型KCNH2共转染(依次为Q1+WT组、Q1+T618I组和Q1+V535M组)。转染后培养48h,提取细胞总RNA和总蛋白,分别应用RT-qPCR和Western Blot方法检测目的基因在mRNA和蛋白水平的相对表达量,比较各组间的差别,同时应用膜片钳技术检测不同功能型KCNH2对KCNQ1电流的影响。
研究结果：
(1)与Sham组相比,HF组兔心室肌细胞KCNH2基因和KCNQ1基因在mRNA水平表达均显著降低(P<0.05)。
(2)与Sham组相比,HF组兔心室肌细胞AP、APD50和APD90均显著延长(P<0.05),其中HF组给予Dof干预后,AP、APD50和APD90均进一步延长(P<0.05),若加用293B共同干预,则AP、APD50和APD90延长程度与单独给予Dof相比增加更显著(P<0.05)。
(3)兔心室肌细胞APA和RMP在Sham组、HF组及给予Dof,293B干预的HF组中无明显差异(P>0.05)。
(4)HF组兔心室肌细胞IKr电流密度与Sham组相比显著降低(P<0.05),给予Dof干预后,两组IKr电流密度均显著下降(P<0.05),且HF组表现更为明显。
(5) Sham组和HF组中,兔心室肌细胞IKr尾电流(IKr,tail)均随刺激脉冲正移不断增加,但HF组增加幅值低于Sham组。给予Dof干预后,两组的IKr,tail均被抑制,随刺激脉冲电压增加抑制效应增强,且对HF组作用更明显。
(6)HF组兔心室肌细胞IKs电流密度与Sham组相比显著降低(P<0.05),给予Dof干预后IKs电流密度显著回升(P<0.05),但未恢复至正常水平。
(7)不同功能型KCNH2与KCNQ1共转染均可使KCNQ1在mRNA水平的相对表达量显著升高(P<0.05),Q1+V535M组升高最显著,Q1+WT组次之,Q1+T618I组升高程度最小。共转染KCNQ1可使不同功能型KCNH2在mRNA水平表达均出现升高,仅野生型升高程度有统计学意义(P<0.05)。
(8)不同功能型KCNH2与KCNQ1共转染均可使KCNQ1在蛋白水平表达升高(P<0.05),其中Q1+T618I组作用最显著,Q1+WT组作用次之,Q1+V535M组作用最弱。共转染KCNQ1可使不同功能型KCNH2在蛋白水平表达均升高,但差异无统计学意义(P>0.05)。
(9)野生型WT-KCNH2与KCNQ1共转染能够使KCNQ1峰电流密度从152.8±7.5pA/pF增加至209.3±9.1pA/pF(P<0.05),功能获得型突变T618I-KCNH2与KCNQ1共转染使KCNQ1峰电流密度升高相对较弱,仅升高至169.2±6.7pA/pF(P<0.05),功能丧失型突变V535M-KCNH2与KCNQ1共转染使KCNQ1峰电流密度升高最为明显,KCNQ1峰电流密度可升高达253.5±13.6pA/pF (P<0.05)
结论：
(1)在mRNA水平,心衰能够使心室肌细胞KCNH2和KCNQ1表达均降低。
(2)心衰时心室肌细胞APD延长,IKr和IKs电流密度降低,复极贮备功能障碍。抑制IKr电流APD延长增加不大,若同时抑制IKr和IKs两种电流,则APD延长显著加重。
(3) KCNH2与KCNQ1均能使彼此在mRNA水平的表达升高,且KCNQ1升高程度与KCNH2的功能呈负相关。
(4)相似地,KCNH2与KCNQ1均能使彼此在蛋白水平的表达升高,且KCNQ1升高程度与KCNH2的功能呈负相关。
(5) KCNH2能够使KCNQ1峰电流密度增加,且升高程度与KCNH2的功能呈负相关。
Background and Aim:The incidence of malignant ventricular arrhythmia and sudden cardiac death increases in heart failure which impairs the quality of the patients'life and even threatens their lives. Recent studies have shown that the increased incidence of heart arrhythmia in heart failure is closely related to the dysfunction of repolarization reserve, in which rapidly activating delayed rectifier potassium current (IKr) and slowly activating delayed rectifier potassium current (IKr) play most important roles in mitigating excessive extension of action potential duration (APD). On one hand, via rabbit heart failure model established by abdominal aorta coarctation, we investigated not only the mRNA expression of KCNH2and KCNQ1in ventricular myocytes in HF, but also the relationship among action potential (AP),IKr channel and IKs channel, in order to research the mechanism of repolarization reserve change in rabbit heart failure model. On the other hand, to research the mechanisms of the interaction between the two important channels in repolarization reserve, we transfected KCNH2and KCNQ1into HEK293cells and investigated the expression of mRNA and protein of these two genes and the KCNQ1current changes. This study provides experimental and theoretical evidences for the mechanism of malignant ventricular arrhythmia and sudden cardiac death in heart failure.
Methods:Twenty-four rabbits were divided randomly into sham operation (Sham) and heart failure (HF) groups, twelve in each. Abdominal aortic coarctation was performed in group HF. After surgery, each rabbit was raised for twelve weeks. And general physical conditions, signs and various indicators of heart function under cardiac ultrasound were evaluated. Then hearts were removed from alive rabbits, and ventricular myocytes were isolated by enzymatic method. Total cellular RNA was extracted, and RT-qPCR was performed to compare the differences of KCNH2and KCNQ1between HF and Sham groups in the level of mRNA. Action potential (AP),IKr and IKs were recorded by whole-cell patch clamp technique with or without drugs dofetilide (Dof) and293B. Action potential duration at50%repolarization (APD50), action potential duration at90%repolarization (APD90), action potential amplitude (APA) and resting membrane potential (RMP) were all compared in different conditions. According to the transient transfection of different genes, HEK293cells were divided into seven groups:KCNQ1(Ql), WT-KCNH2(WT), T618I-KCNH2(gain of function mutation, T618I), V535M-KCNH2(loss of function mutation, V535M), and co-transfection KCNQ1with WT-KCNH2(Q1+WT), T618I-KCNH2(Q1+T618I), and V535M-KCNH2(Q1+V535M) groups. After gene transfection, HEK293cells were incubated for48hours. Then total RNA and protein were extracted, detected by RT-qPCR and Western blot, respectively. KCNQ1current changes induced by different functional KCNH2were recording by whole-cell patch clamp technique.
Results:
(1) Compared with group Sham, mRNA expressions of KCNH2and KCNQ1in ventricular myocytes of the rabbits with HF were decreased (P<0.05).
(2) APD50and APD90were prolonged significantly in ventricular myocytes in group HF (P<0.05). The prolongation of APD50and APD90in HF group with both Dof and293B were more significant than those of using only Dof or without any drug (P<0.05).
(3) APA and RMP in groups Sham or HF, with or without Dof and293B, had no significant differences (P>0.05).
(4) Compared with group Sham, the density of IKr current was reduced in group HF (P<0.05). These effects were aggravated when Dof was used (P<0.05).
(5) In groups Sham and HF, the density of IKr tail current (IKr,tail) increased along with the increment of test potentials,IKr,tail in group HF was lower than that in group Sham at the same test potential. And IKr,tail was inhibited by using Dof in both groups.
(6) Compared with group Sham, the density of IKs current was reduced in group HF (P<0.05). And the effect was significantly diminished when Dof was used (P<0.05), but still lower than Sham.
(7) The relative mRNA expression of KCNQ1in groups with co-transfection of different functional KCNH2was significantly increased than that in group Q1(P<0.05). Among three groups with co-transfection of KCNQ1and KCNH2, the relative mRNA expression of KCNQ1was highest in group Q1+V535M and lowest in group Q1+T618I. The relative mRNA expression of different functional KCNH2was increased with co-transfection of KCNQ1.
(8) Compared with Q1, the relative protein expression of KCNQ1was increased when KCNQ1was co-transfected with different functional KCNH2(P<0.05). Among co-transfection groups, the relative protein expression of KCNQ1was higher in Q1+V535M group and lower in Q1+T618I than Q1+WT. Co-transfection of KCNQ1increased the relative protein expression of different functional KCNH2.
(9) With co-transfenction of WT-KCNH2increased the KCNQ1current densities from152.8±7.5pA/pF to209.3±9.1pA/pF (P<0.05). Compared with group Q1, the KCNQ1current density in group Q1+T618I was slightly increased to169.2±6.7pA/pF (P<0.05), and the KCNQ1current density in group Q1+V535M was much more increased and up to253.5±13.6pA/pF (P<0.05).
Conclusion:
(1) Heart failure reduced the relative mRNA expression of KCNH2and KCNQ1.
(2) APD was prolonged and the densities of IKr and IKs current were lower in ventricular myocytes of rabbits with heart failure, which impaired the repolarization reserve. The manifestations were getting worse by inhibiting IKr and IKs.
(3) KCNQ1and KCNH2in three functional forms increased the relative mRNA expression of each other.
(4) Analogously, different functional KCNH2and KCNQ1also increased the relative protein expression of each other.
(5) KCNH2significantly increased KCNQ1current density, and the KCNQ1current density in group Q1+V535M was increased most among three co-transfection groups.
研究方法：24只日本大耳白兔随机分为假手术组(Sham)和心衰模型组(HF),每组12只,分别行腹主动脉分离术和腹主动脉缩窄术,术后常规饲养12周,评价一般情况及心脏超声指标,判定HF组模型建立达标情况。Sham组与HF组动物均麻醉取心脏,灌流分离心室肌细胞,提取总RNA用RT-qPCR方法,比较目的基因KCNH2及KCNQ1的mRNA表达量在两组间的差别,应用膜片钳技术辅以钾离子通道阻滞剂多非利特(Dof)和293B药物,检测心衰时心室肌细胞AP,比较复极至50%的动作电位时程(APD50)、复极至90%的动作电位时程(APD90)、动作电位幅值(APA)和静息膜电位(RMP)在各条件下的变化情况,测定心室肌细胞IKr电流和IKs电流在不同条件下的改变。另一方面应用瞬时转染技术,将HEK293细胞随机分为7组,即单独将KCNQ1(Q1组)、野生型WT-KCNH2(WT组)、功能获得型T618I-KCNH2(T618I组)和功能缺失型V535M-KCNH2(V535M组)与空质粒共转染,及将KCNQ1分别与各功能型KCNH2共转染(依次为Q1+WT组、Q1+T618I组和Q1+V535M组)。转染后培养48h,提取细胞总RNA和总蛋白,分别应用RT-qPCR和Western Blot方法检测目的基因在mRNA和蛋白水平的相对表达量,比较各组间的差别,同时应用膜片钳技术检测不同功能型KCNH2对KCNQ1电流的影响。
研究结果：
(1)与Sham组相比,HF组兔心室肌细胞KCNH2基因和KCNQ1基因在mRNA水平表达均显著降低(P<0.05)。
(2)与Sham组相比,HF组兔心室肌细胞AP、APD50和APD90均显著延长(P<0.05),其中HF组给予Dof干预后,AP、APD50和APD90均进一步延长(P<0.05),若加用293B共同干预,则AP、APD50和APD90延长程度与单独给予Dof相比增加更显著(P<0.05)。
(3)兔心室肌细胞APA和RMP在Sham组、HF组及给予Dof,293B干预的HF组中无明显差异(P>0.05)。
(4)HF组兔心室肌细胞IKr电流密度与Sham组相比显著降低(P<0.05),给予Dof干预后,两组IKr电流密度均显著下降(P<0.05),且HF组表现更为明显。
(5) Sham组和HF组中,兔心室肌细胞IKr尾电流(IKr,tail)均随刺激脉冲正移不断增加,但HF组增加幅值低于Sham组。给予Dof干预后,两组的IKr,tail均被抑制,随刺激脉冲电压增加抑制效应增强,且对HF组作用更明显。
(6)HF组兔心室肌细胞IKs电流密度与Sham组相比显著降低(P<0.05),给予Dof干预后IKs电流密度显著回升(P<0.05),但未恢复至正常水平。
(7)不同功能型KCNH2与KCNQ1共转染均可使KCNQ1在mRNA水平的相对表达量显著升高(P<0.05),Q1+V535M组升高最显著,Q1+WT组次之,Q1+T618I组升高程度最小。共转染KCNQ1可使不同功能型KCNH2在mRNA水平表达均出现升高,仅野生型升高程度有统计学意义(P<0.05)。
(8)不同功能型KCNH2与KCNQ1共转染均可使KCNQ1在蛋白水平表达升高(P<0.05),其中Q1+T618I组作用最显著,Q1+WT组作用次之,Q1+V535M组作用最弱。共转染KCNQ1可使不同功能型KCNH2在蛋白水平表达均升高,但差异无统计学意义(P>0.05)。
(9)野生型WT-KCNH2与KCNQ1共转染能够使KCNQ1峰电流密度从152.8±7.5pA/pF增加至209.3±9.1pA/pF(P<0.05),功能获得型突变T618I-KCNH2与KCNQ1共转染使KCNQ1峰电流密度升高相对较弱,仅升高至169.2±6.7pA/pF(P<0.05),功能丧失型突变V535M-KCNH2与KCNQ1共转染使KCNQ1峰电流密度升高最为明显,KCNQ1峰电流密度可升高达253.5±13.6pA/pF (P<0.05)
结论：
(1)在mRNA水平,心衰能够使心室肌细胞KCNH2和KCNQ1表达均降低。
(2)心衰时心室肌细胞APD延长,IKr和IKs电流密度降低,复极贮备功能障碍。抑制IKr电流APD延长增加不大,若同时抑制IKr和IKs两种电流,则APD延长显著加重。
(3) KCNH2与KCNQ1均能使彼此在mRNA水平的表达升高,且KCNQ1升高程度与KCNH2的功能呈负相关。
(4)相似地,KCNH2与KCNQ1均能使彼此在蛋白水平的表达升高,且KCNQ1升高程度与KCNH2的功能呈负相关。
(5) KCNH2能够使KCNQ1峰电流密度增加,且升高程度与KCNH2的功能呈负相关。
Background and Aim:The incidence of malignant ventricular arrhythmia and sudden cardiac death increases in heart failure which impairs the quality of the patients'life and even threatens their lives. Recent studies have shown that the increased incidence of heart arrhythmia in heart failure is closely related to the dysfunction of repolarization reserve, in which rapidly activating delayed rectifier potassium current (IKr) and slowly activating delayed rectifier potassium current (IKr) play most important roles in mitigating excessive extension of action potential duration (APD). On one hand, via rabbit heart failure model established by abdominal aorta coarctation, we investigated not only the mRNA expression of KCNH2and KCNQ1in ventricular myocytes in HF, but also the relationship among action potential (AP),IKr channel and IKs channel, in order to research the mechanism of repolarization reserve change in rabbit heart failure model. On the other hand, to research the mechanisms of the interaction between the two important channels in repolarization reserve, we transfected KCNH2and KCNQ1into HEK293cells and investigated the expression of mRNA and protein of these two genes and the KCNQ1current changes. This study provides experimental and theoretical evidences for the mechanism of malignant ventricular arrhythmia and sudden cardiac death in heart failure.
Methods:Twenty-four rabbits were divided randomly into sham operation (Sham) and heart failure (HF) groups, twelve in each. Abdominal aortic coarctation was performed in group HF. After surgery, each rabbit was raised for twelve weeks. And general physical conditions, signs and various indicators of heart function under cardiac ultrasound were evaluated. Then hearts were removed from alive rabbits, and ventricular myocytes were isolated by enzymatic method. Total cellular RNA was extracted, and RT-qPCR was performed to compare the differences of KCNH2and KCNQ1between HF and Sham groups in the level of mRNA. Action potential (AP),IKr and IKs were recorded by whole-cell patch clamp technique with or without drugs dofetilide (Dof) and293B. Action potential duration at50%repolarization (APD50), action potential duration at90%repolarization (APD90), action potential amplitude (APA) and resting membrane potential (RMP) were all compared in different conditions. According to the transient transfection of different genes, HEK293cells were divided into seven groups:KCNQ1(Ql), WT-KCNH2(WT), T618I-KCNH2(gain of function mutation, T618I), V535M-KCNH2(loss of function mutation, V535M), and co-transfection KCNQ1with WT-KCNH2(Q1+WT), T618I-KCNH2(Q1+T618I), and V535M-KCNH2(Q1+V535M) groups. After gene transfection, HEK293cells were incubated for48hours. Then total RNA and protein were extracted, detected by RT-qPCR and Western blot, respectively. KCNQ1current changes induced by different functional KCNH2were recording by whole-cell patch clamp technique.
Results:
(1) Compared with group Sham, mRNA expressions of KCNH2and KCNQ1in ventricular myocytes of the rabbits with HF were decreased (P<0.05).
(2) APD50and APD90were prolonged significantly in ventricular myocytes in group HF (P<0.05). The prolongation of APD50and APD90in HF group with both Dof and293B were more significant than those of using only Dof or without any drug (P<0.05).
(3) APA and RMP in groups Sham or HF, with or without Dof and293B, had no significant differences (P>0.05).
(4) Compared with group Sham, the density of IKr current was reduced in group HF (P<0.05). These effects were aggravated when Dof was used (P<0.05).
(5) In groups Sham and HF, the density of IKr tail current (IKr,tail) increased along with the increment of test potentials,IKr,tail in group HF was lower than that in group Sham at the same test potential. And IKr,tail was inhibited by using Dof in both groups.
(6) Compared with group Sham, the density of IKs current was reduced in group HF (P<0.05). And the effect was significantly diminished when Dof was used (P<0.05), but still lower than Sham.
(7) The relative mRNA expression of KCNQ1in groups with co-transfection of different functional KCNH2was significantly increased than that in group Q1(P<0.05). Among three groups with co-transfection of KCNQ1and KCNH2, the relative mRNA expression of KCNQ1was highest in group Q1+V535M and lowest in group Q1+T618I. The relative mRNA expression of different functional KCNH2was increased with co-transfection of KCNQ1.
(8) Compared with Q1, the relative protein expression of KCNQ1was increased when KCNQ1was co-transfected with different functional KCNH2(P<0.05). Among co-transfection groups, the relative protein expression of KCNQ1was higher in Q1+V535M group and lower in Q1+T618I than Q1+WT. Co-transfection of KCNQ1increased the relative protein expression of different functional KCNH2.
(9) With co-transfenction of WT-KCNH2increased the KCNQ1current densities from152.8±7.5pA/pF to209.3±9.1pA/pF (P<0.05). Compared with group Q1, the KCNQ1current density in group Q1+T618I was slightly increased to169.2±6.7pA/pF (P<0.05), and the KCNQ1current density in group Q1+V535M was much more increased and up to253.5±13.6pA/pF (P<0.05).
Conclusion:
(1) Heart failure reduced the relative mRNA expression of KCNH2and KCNQ1.
(2) APD was prolonged and the densities of IKr and IKs current were lower in ventricular myocytes of rabbits with heart failure, which impaired the repolarization reserve. The manifestations were getting worse by inhibiting IKr and IKs.
(3) KCNQ1and KCNH2in three functional forms increased the relative mRNA expression of each other.
(4) Analogously, different functional KCNH2and KCNQ1also increased the relative protein expression of each other.
(5) KCNH2significantly increased KCNQ1current density, and the KCNQ1current density in group Q1+V535M was increased most among three co-transfection groups.
引文
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