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Article: Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers

TitleOverexpression of HCN-encoded pacemaker current silences bioartificial pacemakers
Authors
KeywordsGene transfer
HCN channel
Pacemaker
Issue Date2008
PublisherElsevier 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?
AbstractBackground: 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 Identifierhttp://hdl.handle.net/10722/91695
ISSN
2015 Impact Factor: 4.391
2015 SCImago Journal Rankings: 2.756
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthR01-HL72857
University of California
Hong Kong Research Grant CouncilHKU 7459/04M
University of Hong Kong
Shriners Hospital for Children
Croucher Foundation
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 FieldValueLanguage
dc.contributor.authorLieu, DKen_HK
dc.contributor.authorChan, YCen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorSiu, CWen_HK
dc.contributor.authorLi, RAen_HK
dc.date.accessioned2010-09-17T10:23:29Z-
dc.date.available2010-09-17T10:23:29Z-
dc.date.issued2008en_HK
dc.identifier.citationHeart Rhythm, 2008, v. 5 n. 9, p. 1310-1317en_HK
dc.identifier.issn1547-5271en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91695-
dc.description.abstractBackground: 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.languageengen_HK
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/heartrhythmjournalen_HK
dc.relation.ispartofHeart Rhythmen_HK
dc.rightsHeart Rhythm. Copyright © Elsevier Inc.-
dc.subjectGene transferen_HK
dc.subjectHCN channelen_HK
dc.subjectPacemakeren_HK
dc.subject.meshAtrial Function - physiology-
dc.subject.meshCardiac Pacing, Artificial-
dc.subject.meshCyclic Nucleotide-Gated Cation Channels - drug effects-
dc.subject.meshHeart Atria - cytology - innervation-
dc.subject.meshHeart Ventricles - cytology - innervation-
dc.titleOverexpression of HCN-encoded pacemaker current silences bioartificial pacemakersen_HK
dc.typeArticleen_HK
dc.identifier.emailChan, YC:yauchi@graduate.hku.hken_HK
dc.identifier.emailTse, HF:hftse@hkucc.hku.hken_HK
dc.identifier.emailSiu, CW:cwdsiu@hkucc.hku.hken_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityChan, YC=rp01502en_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authoritySiu, CW=rp00534en_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.hrthm.2008.05.010en_HK
dc.identifier.pmid18693074-
dc.identifier.scopuseid_2-s2.0-50849099151en_HK
dc.identifier.hkuros182847-
dc.identifier.hkuros151392-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-50849099151&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume5en_HK
dc.identifier.issue9en_HK
dc.identifier.spage1310en_HK
dc.identifier.epage1317en_HK
dc.identifier.isiWOS:000259281600016-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectFunctional role of pacemaker current, I(f) in sinoatrial node probed by somatic gene transfer of bioengineered HCN channels in swine-
dc.identifier.scopusauthoridLieu, DK=7003924538en_HK
dc.identifier.scopusauthoridChan, YC=7403676116en_HK
dc.identifier.scopusauthoridLau, CP=7401968501en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridSiu, CW=7006550690en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK

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