Document Detail


Size and ionic currents of unexcitable cells coupled to cardiomyocytes distinctly modulate cardiac action potential shape and pacemaking activity in micropatterned cell pairs.
MedLine Citation:
PMID:  22679057     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Cardiac cell therapies can yield electric coupling of unexcitable donor cells to host cardiomyocytes with functional consequences that remain unexplored.
METHODS AND RESULTS: We micropatterned cell pairs consisting of a neonatal rat ventricular myocyte (NRVM) coupled to an engineered human embryonic kidney 293 (HEK293) cell expressing either connexin-43 (Cx43 HEK) or inward rectifier potassium channel 2.1 (Kir2.1) and Cx43 (Kir2.1+Cx43 HEK). The NRVM-HEK contact length was fixed yielding a coupling strength of 68.9±9.7 nS, whereas HEK size was systematically varied. With increase in Cx43 HEK size, NRVM maximal diastolic potential was reduced from -71.7±0.6 mV in single NRVMs to -35.1±1.3 mV in pairs with an HEK:NRVM cell surface area ratio of 1.7±0.1, whereas the action potential upstroke ([dV(m)/dt](max)) and duration decreased to 1.6±0.7% and increased to 177±32% in single NRVM values, respectively (n=21 cell pairs). Pacemaking occurred in all NRVM-Cx43 HEK pairs with cell surface area ratios of 1.1 to 1.9. In contrast, NRVMs, coupled with Kir2.1+Cx43 HEKs of increasing size, had similar maximal diastolic potentials, exhibited no spontaneous activity, and showed a gradual decrease in action potential duration (n=23). Furthermore, coupling single NRVMs to a dynamic clamp model of HEK cell ionic current reproduced the cardiac maximal diastolic potentials and pacemaking rates recorded in cell pairs, whereas reproducing changes in (dV(m)/dt)(max) and action potential duration required coupling to an HEK model that also included cell membrane capacitance.
CONCLUSIONS: Size and ionic currents of unexcitable cells electrically coupled to cardiomyocytes distinctly affect cardiac action potential shape and initiation with important implications for the safety of cardiac cell and gene therapies.
Authors:
Luke C McSpadden; Hung Nguyen; Nenad Bursac
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-07
Journal Detail:
Title:  Circulation. Arrhythmia and electrophysiology     Volume:  5     ISSN:  1941-3084     ISO Abbreviation:  Circ Arrhythm Electrophysiol     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-16     Completed Date:  2012-10-26     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  101474365     Medline TA:  Circ Arrhythm Electrophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  821-30     Citation Subset:  IM    
Affiliation:
Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
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MeSH Terms
Descriptor/Qualifier:
Action Potentials
Animals
Animals, Newborn
Biological Clocks*
Cell Communication*
Cell Size
Coculture Techniques
Connexin 43 / genetics,  metabolism
Electric Capacitance
Electric Impedance
Epithelial Cells / metabolism*
Fibronectins / metabolism
HEK293 Cells
Humans
Microscopy, Confocal
Myocardial Contraction*
Myocytes, Cardiac / metabolism*
Patch-Clamp Techniques
Potassium Channels, Inwardly Rectifying / genetics,  metabolism
Rats
Rats, Sprague-Dawley
Time Factors
Transfection
Video Recording
Grant Support
ID/Acronym/Agency:
HL104326/HL/NHLBI NIH HHS; HL106203/HL/NHLBI NIH HHS; R01 HL104326/HL/NHLBI NIH HHS; R21 HL106203/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Connexin 43; 0/Fibronectins; 0/KCNJ2 protein, human; 0/Potassium Channels, Inwardly Rectifying
Comments/Corrections

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