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Cardiovascular Research Advance Access first published online on January 28, 2009
This version [Corrected Proof] published online on February 19, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp028
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Human cardiac gap-junction coupling: effects of antiarrhythmic peptide AAP10

Anja Hagen*, Anna Dietze and Stefan Dhein

Clinic for Cardiac Surgery, University of Leipzig, Heart Centre, Strümpellstr. 39, 04289 Leipzig, Germany

* Corresponding author. University of Leipzig, University Hospital for Children and Adolescents, Liebigstr. 20a, 04103 Leipzig, Germany. Tel: +49 341 9726000; fax: +49 341 9726009. E-mail address: anja.hagen{at}medizin.uni-leipzig.de

Aims: Ventricular arrhythmia is one of the most important causes of death in industrialized countries and often accompanies myocardial infarction and heart failure. In recent years modification of gap-junctional coupling has been proposed as a new antiarrhythmic principle. We wanted to examine whether the gap junction modulator (antiarrhythmic peptide) AAP10 exerts effects on human cardiac gap junctions, whether the effect might be enhanced in uncoupled cells, whether it affects electrical and metabolic coupling, and which of the cardiac connexin isoforms (Cx40, Cx43, Cx45) may be affected.

Methods and results: We determined the influence of 50 nM AAP10 (H2N-Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH2) on macroscopic gap junction conductance by dual whole-cell voltage clamping in human and rat cardiomyocytes. Cells were partially uncoupled by CO2-mediated acidosis (pH 6.3) or kept at ‘normal’ conditions (pH 7.4, T 36°C). Furthermore, we investigated effects of AAP10 in HeLa cells stably transfected with connexin 40, 43, or 45 and on metabolic coupling determined by dye transfer (Lucifer yellow). AAP10 (50 nM)-enhanced gap-junctional intercellular coupling in human and rat cardiomyocytes, completely prevented CO2-acidosis-induced uncoupling and improved metabolic coupling. The coupling effect of AAP10 was significantly enhanced in previously uncoupled cells. Regarding the connexin isoforms, AAP10-enhanced electrical and metabolic coupling in HeLa cells expressing Cx43 or Cx45, but not in HeLa cells expressing Cx40.

Conclusion: We conclude that the antiarrhythmic peptide AAP10, which improves gap-junctional intercellular coupling and prevents uncoupling by acidification in human cardiomyocytes, might be useful for antiarrhythmic strategies regarding arrhythmias caused by uncoupling of Cx43 and Cx45, but not Cx40.

KEYWORDS Antiarrhythmic peptide; AAP10; Gap junctions; Human cardiomyocytes; Dual whole-cell voltage clamp

Time for primary review: 18 days


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