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- Publisher Website: 10.1016/j.hrthm.2008.05.010
- Scopus: eid_2-s2.0-50849099151
- PMID: 18693074
- WOS: WOS:000259281600016
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Article: Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers
Title | Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers | ||||||||||||||
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Authors | |||||||||||||||
Keywords | Gene transfer HCN channel Pacemaker | ||||||||||||||
Issue Date | 2008 | ||||||||||||||
Publisher | Elsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/heartrhythmjournal | ||||||||||||||
Citation | Heart Rhythm, 2008, v. 5 n. 9, p. 1310-1317 How to Cite? | ||||||||||||||
Abstract | Background: Current strategies of engineering bioartificial pacemakers from otherwise silent yet excitable adult atrial and ventricular cardiomyocytes primarily rely on either maximizing the hyperpolarization-activated If or on minimizing its presumptive opponent, the inwardly rectifying potassium current IK1. Objective: The purpose of this study was to determine quantitatively the relative current densities of If and IK1 necessary to induce automaticity in adult atrial cardiomyocytes. Methods: Automaticity of adult guinea pig atrial cardiomyocytes was induced by adenovirus (Ad)-mediated overexpression of the gating-engineered HCN1 construct HCN1-ΔΔΔ with the S3-S4 linker residues EVY235-7 deleted to favor channel opening. Results: Whereas control atrial cardiomyocytes remained electrically quiescent and had no If, 18% of Ad-CMV-GFP-IRES-HCN1-ΔΔΔ (Ad-CGI-HCN1-ΔΔΔ)-transduced cells demonstrated automaticity (240 ± 14 bpm) with gradual phase 4 depolarization (143 ± 28 mV/s), a depolarized maximal diastolic potential (-45.3 ± 2.2 mV), and substantial If at -140 mV (If,-140 mV = -9.32 ± 1.84 pA/pF). In the remaining quiescent Ad-CGI-HCN1-ΔΔΔ-transduced atrial cardiomyocytes, two distinct immediate phenotypes were observed: (1) 13% had a hyperpolarized resting membrane potential (-56.7 ± 1.3 mV) with If,-140 mV of -4.85 ± 0.97 pA/pF; and (2) the remaining 69% displayed a depolarized resting membrane potential (-27.6 ± 1.3 mV) with If,-140 mV of -23.0 ± 3.71 pA/pF. Upon electrical stimulation, both quiescent groups elicited a single action potential with incomplete phase 4 depolarization that was never seen in controls. Further electrophysiologic analysis indicates that an intricate balance of IK1 and If is necessary for induction of atrial automaticity. Conclusion: Optimized pacing induction and modulation can be better achieved by engineering the If/IK1 ratio rather than the individual currents. © 2008 Heart Rhythm Society. | ||||||||||||||
Persistent Identifier | http://hdl.handle.net/10722/91695 | ||||||||||||||
ISSN | 2023 Impact Factor: 5.6 2023 SCImago Journal Rankings: 2.072 | ||||||||||||||
ISI Accession Number ID |
Funding Information: This work was supported by grants from the National Institutes of Health (R01-HL72857) to Dr. Li, from the Stem Cell program of the University of California to Dr. Li, and from the Hong Kong Research Grant Council (HKU 7459/04M) to Drs. Lau, Tse, and Li. Dr. Chan was supported by a postgraduate studentship from the University of Hong Kong Dr. Lieu was supported by a fellowship from the Shriners Hospital for Children. Dr. Sin was supported by a postdoctoral fellowship award from the Croucher Foundation. Drs. Lieu. Chan. and Siu contributed equally to this work. | ||||||||||||||
References | |||||||||||||||
Grants |
DC Field | Value | Language |
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dc.contributor.author | Lieu, DK | en_HK |
dc.contributor.author | Chan, YC | en_HK |
dc.contributor.author | Lau, CP | en_HK |
dc.contributor.author | Tse, HF | en_HK |
dc.contributor.author | Siu, CW | en_HK |
dc.contributor.author | Li, RA | en_HK |
dc.date.accessioned | 2010-09-17T10:23:29Z | - |
dc.date.available | 2010-09-17T10:23:29Z | - |
dc.date.issued | 2008 | en_HK |
dc.identifier.citation | Heart Rhythm, 2008, v. 5 n. 9, p. 1310-1317 | en_HK |
dc.identifier.issn | 1547-5271 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/91695 | - |
dc.description.abstract | Background: Current strategies of engineering bioartificial pacemakers from otherwise silent yet excitable adult atrial and ventricular cardiomyocytes primarily rely on either maximizing the hyperpolarization-activated If or on minimizing its presumptive opponent, the inwardly rectifying potassium current IK1. Objective: The purpose of this study was to determine quantitatively the relative current densities of If and IK1 necessary to induce automaticity in adult atrial cardiomyocytes. Methods: Automaticity of adult guinea pig atrial cardiomyocytes was induced by adenovirus (Ad)-mediated overexpression of the gating-engineered HCN1 construct HCN1-ΔΔΔ with the S3-S4 linker residues EVY235-7 deleted to favor channel opening. Results: Whereas control atrial cardiomyocytes remained electrically quiescent and had no If, 18% of Ad-CMV-GFP-IRES-HCN1-ΔΔΔ (Ad-CGI-HCN1-ΔΔΔ)-transduced cells demonstrated automaticity (240 ± 14 bpm) with gradual phase 4 depolarization (143 ± 28 mV/s), a depolarized maximal diastolic potential (-45.3 ± 2.2 mV), and substantial If at -140 mV (If,-140 mV = -9.32 ± 1.84 pA/pF). In the remaining quiescent Ad-CGI-HCN1-ΔΔΔ-transduced atrial cardiomyocytes, two distinct immediate phenotypes were observed: (1) 13% had a hyperpolarized resting membrane potential (-56.7 ± 1.3 mV) with If,-140 mV of -4.85 ± 0.97 pA/pF; and (2) the remaining 69% displayed a depolarized resting membrane potential (-27.6 ± 1.3 mV) with If,-140 mV of -23.0 ± 3.71 pA/pF. Upon electrical stimulation, both quiescent groups elicited a single action potential with incomplete phase 4 depolarization that was never seen in controls. Further electrophysiologic analysis indicates that an intricate balance of IK1 and If is necessary for induction of atrial automaticity. Conclusion: Optimized pacing induction and modulation can be better achieved by engineering the If/IK1 ratio rather than the individual currents. © 2008 Heart Rhythm Society. | en_HK |
dc.language | eng | en_HK |
dc.publisher | Elsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/heartrhythmjournal | en_HK |
dc.relation.ispartof | Heart Rhythm | en_HK |
dc.rights | Heart Rhythm. Copyright © Elsevier Inc. | - |
dc.subject | Gene transfer | en_HK |
dc.subject | HCN channel | en_HK |
dc.subject | Pacemaker | en_HK |
dc.subject.mesh | Atrial Function - physiology | - |
dc.subject.mesh | Cardiac Pacing, Artificial | - |
dc.subject.mesh | Cyclic Nucleotide-Gated Cation Channels - drug effects | - |
dc.subject.mesh | Heart Atria - cytology - innervation | - |
dc.subject.mesh | Heart Ventricles - cytology - innervation | - |
dc.title | Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers | en_HK |
dc.type | Article | en_HK |
dc.identifier.email | Chan, YC:yauchi@graduate.hku.hk | en_HK |
dc.identifier.email | Tse, HF:hftse@hkucc.hku.hk | en_HK |
dc.identifier.email | Siu, CW:cwdsiu@hkucc.hku.hk | en_HK |
dc.identifier.email | Li, RA:ronaldli@hkucc.hku.hk | en_HK |
dc.identifier.authority | Chan, YC=rp01502 | en_HK |
dc.identifier.authority | Tse, HF=rp00428 | en_HK |
dc.identifier.authority | Siu, CW=rp00534 | en_HK |
dc.identifier.authority | Li, RA=rp01352 | en_HK |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1016/j.hrthm.2008.05.010 | en_HK |
dc.identifier.pmid | 18693074 | - |
dc.identifier.scopus | eid_2-s2.0-50849099151 | en_HK |
dc.identifier.hkuros | 182847 | - |
dc.identifier.hkuros | 151392 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-50849099151&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 5 | en_HK |
dc.identifier.issue | 9 | en_HK |
dc.identifier.spage | 1310 | en_HK |
dc.identifier.epage | 1317 | en_HK |
dc.identifier.isi | WOS:000259281600016 | - |
dc.publisher.place | United States | en_HK |
dc.relation.project | Functional role of pacemaker current, I(f) in sinoatrial node probed by somatic gene transfer of bioengineered HCN channels in swine | - |
dc.identifier.scopusauthorid | Lieu, DK=7003924538 | en_HK |
dc.identifier.scopusauthorid | Chan, YC=7403676116 | en_HK |
dc.identifier.scopusauthorid | Lau, CP=7401968501 | en_HK |
dc.identifier.scopusauthorid | Tse, HF=7006070805 | en_HK |
dc.identifier.scopusauthorid | Siu, CW=7006550690 | en_HK |
dc.identifier.scopusauthorid | Li, RA=7404724466 | en_HK |
dc.identifier.issnl | 1547-5271 | - |