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本文引用的文献

1
Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers.HCN编码的起搏电流过表达使生物人工起搏器失活。
Heart Rhythm. 2008 Sep;5(9):1310-7. doi: 10.1016/j.hrthm.2008.05.010. Epub 2008 May 15.
2
Structural and functional determinants in the S5-P region of HCN-encoded pacemaker channels revealed by cysteine-scanning substitutions.通过半胱氨酸扫描替换揭示的HCN编码的起搏器通道S5-P区域的结构和功能决定因素。
Am J Physiol Cell Physiol. 2008 Jan;294(1):C136-44. doi: 10.1152/ajpcell.00340.2007. Epub 2007 Nov 7.
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HCN-encoded pacemaker channels: from physiology and biophysics to bioengineering.HCN编码的起搏器通道:从生理与生物物理学到生物工程学
J Membr Biol. 2006;214(3):115-22. doi: 10.1007/s00232-006-0881-9. Epub 2007 Jun 8.
4
New insights into pacemaker activity: promoting understanding of sick sinus syndrome.起搏器活动的新见解:促进对病态窦房结综合征的理解。
Circulation. 2007 Apr 10;115(14):1921-32. doi: 10.1161/CIRCULATIONAHA.106.616011.
5
Mechanistic role of I(f) revealed by induction of ventricular automaticity by somatic gene transfer of gating-engineered pacemaker (HCN) channels.通过门控工程化起搏器(HCN)通道的体细胞基因转移诱导心室自律性所揭示的I(f)的机制作用。
Circulation. 2007 Apr 10;115(14):1839-50. doi: 10.1161/CIRCULATIONAHA.106.659391. Epub 2007 Mar 26.
6
Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN Channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model.通过工程化起搏器HCN通道的体内基因转移构建的生物人工窦房结可降低病态窦房结综合征模型对电子起搏器的依赖。
Circulation. 2006 Sep 5;114(10):1000-11. doi: 10.1161/CIRCULATIONAHA.106.615385. Epub 2006 Aug 21.
7
Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker.串联式生物电子心脏起搏器中的野生型和突变型HCN通道
Circulation. 2006 Sep 5;114(10):992-9. doi: 10.1161/CIRCULATIONAHA.106.617613. Epub 2006 Aug 21.
8
Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.与心脏起搏器通道突变相关的家族性窦性心动过缓。
N Engl J Med. 2006 Jan 12;354(2):151-7. doi: 10.1056/NEJMoa052475.
9
Non-equilibrium behavior of HCN channels: insights into the role of HCN channels in native and engineered pacemakers.HCN通道的非平衡行为:对HCN通道在天然和工程化起搏器中作用的见解。
Cardiovasc Res. 2005 Aug 1;67(2):263-73. doi: 10.1016/j.cardiores.2005.03.006. Epub 2005 Apr 21.
10
The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis.内向整流电流(IK1)控制心脏兴奋性并参与心律失常的发生。
Heart Rhythm. 2005 Mar;2(3):316-24. doi: 10.1016/j.hrthm.2004.11.012.

内向整流(I)电流和起搏(I)电流对生物工程心脏自动性诱导的协同作用。

Synergistic effects of inward rectifier (I) and pacemaker (I) currents on the induction of bioengineered cardiac automaticity.

作者信息

Chan Yau-Chi, Siu Chung-Wah, Lau Yee-Man, Lau Chu-Pak, Li Ronald A, Tse Hung-Fat

机构信息

Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong.

出版信息

J Cardiovasc Electrophysiol. 2009 Sep;20(9):1048-54. doi: 10.1111/j.1540-8167.2009.01475.x.

DOI:10.1111/j.1540-8167.2009.01475.x
PMID:19460073
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2739246/
Abstract

INTRODUCTION

Normal heart rhythms originate in the sinoatrial node. HCN-encoded funny current (I(f)) and the Kir2-encoded inward rectifier (I(K1)) counteract each other by respectively oscillating and stabilizing the negative resting membrane potential, and controlling action potential firing. Therefore, I(K1) suppression and I(f) overexpression have been independently exploited to convert cardiomyocytes (CMs) into AP-firing bioartificial pacemakers. Although the 2 strategies have been largely assumed synergistic, their complementarity has not been investigated.

METHODS AND RESULTS

We explored the interrelationships of automaticity, I(f) and I(K1) by transducing single left ventricular (LV) CMs isolated from guinea pig hearts with the recombinant adenoviruses Ad-CMV-GFP-IRES-HCN1-AAA and/or Ad-CGI-Kir2.1 to mediate their current densities via a whole-cell patch clamp technique at 37 degrees C. Results showed that Ad-CGI-HCN1-AAA but not Ad-CGI-Kir2.1 transduction induced automaticity (181.1 +/- 13.1 bpm). Interestingly, Ad-CGI-HCN1-AAA/Ad-CGI-Kir2.1 cotransduction significantly promoted the induced firing frequency (320.0 +/- 15.8 bpm; P < 0.05). Correlation analysis revealed that the firing frequency, phase-4 slope and APD(90) of AP-firing LV CMs were correlated with I(f) (R(2) > 0.7) only when -2 >I(K1) >-4 pA/pF but not with I(K1) over the entire I(f) ranges examined (0.02 < R(2) < 0.4). Unlike I(f), I(K1) displayed correlation with neither the phase-4 slope (R(2)= 0.02) nor phase-4 length (R(2)= 0.04) when -2 > I(f) > -4 pA/pF. As anticipated, however, APD(90) was correlated with I(K1) (R(2)= 0.4).

CONCLUSION

We conclude that an optimal level of I(K1) maintains a voltage range for I(f) to operate most effectively during a dynamic cardiac cycle.

摘要

引言

正常心脏节律起源于窦房结。由HCN编码的超极化激活的阳离子电流(I(f))和由Kir2编码的内向整流钾电流(I(K1))通过分别使静息膜电位振荡和稳定以及控制动作电位发放来相互拮抗。因此,I(K1)抑制和I(f)过表达已被分别用于将心肌细胞(CMs)转化为能发放动作电位的生物人工起搏器。尽管这两种策略在很大程度上被认为具有协同作用,但它们的互补性尚未得到研究。

方法与结果

我们通过用重组腺病毒Ad-CMV-GFP-IRES-HCN1-AAA和/或Ad-CGI-Kir2.1转导从豚鼠心脏分离的单个左心室(LV)心肌细胞,在37℃下通过全细胞膜片钳技术调节其电流密度,从而探究自律性、I(f)和I(K1)之间的相互关系。结果显示,Ad-CGI-HCN1-AAA转导而非Ad-CGI-Kir2.1转导诱导了自律性(181.1±13.1次/分钟)。有趣的是,Ad-CGI-HCN1-AAA/Ad-CGI-Kir2.1共转导显著提高了诱导的发放频率(320.0±15.8次/分钟;P<0.05)。相关性分析表明,仅当-2>I(K1)>-4 pA/pF时,发放动作电位的LV心肌细胞的发放频率、4期斜率和动作电位时程(APD(90))与I(f)相关(R(2)>0.7),而在整个检测的I(f)范围内(0.02<R(2)<0.4)与I(K1)无关。与I(f)不同,当-2>I(f)>-4 pA/pF时,I(K1)与4期斜率(R(2)=0.02)和4期长度(R(2)=0.04)均无相关性。然而,正如预期的那样,APD(90)与I(K1)相关(R(2)=0.4)。

结论

我们得出结论,在动态心动周期中,I(K1)的最佳水平维持了I(f)最有效发挥作用的电压范围。