P530Ventricular fibrillation itself down-regulates connexin-43 while sudden increase of its un-phosphorylated form is likely involved in cardioversion demonstrated in perfused rat heart

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Background and Purpose

Ventricular fibrillation (VF) is life-threatening arrhythmia, which occurrence precedes development of myocardial arrhythmogenic substrate resulting from either chronic or acute pathophysiological conditions. Our previous and other studies suggest that down-regulated and/or heterogeneously distributed connexin-43 (Cx43) in diseased or aged heart facilitates occurrence of malignant arrhythmias. We hypothesize that VF itself impairs Cx43 and it may hamper cardioversion into sinus rhythm. The purpose of this study was to examine whether myocardial expression and phosphorylated status of Cx43 is altered due to VF and during sinus rhythm restoration.

Design and Methods

Experiments were performed using 10-mth-old, male and female Wistar rats. Isolated spontaneously-beating heart perfused with oxygenated Krebs-Henseleit solution was subjected to: (1) ten minutes stabilization, (2) electrically-induced VF lasting two minutes, (3) electrically-induced VF lasting ten minutes, 4) two min lasting VF and its termination by stop perfusion followed by spontaneous sinus rhythm restoration. The hearts were snap frozen in liquid N2 at each stage (1,2,3,4) and ventricular tissues were taken for immunobloting of Cx43 using rabbit antiCx43 MAB (Sigma-Aldrich) to detect functional phosphorylated (P) of Cx43 as well as its un-phosphorylated form (noP) and mouse antiCx43 MAB (Zymed) to detect noP Cx43 only.


Total Cx43 expression did not change significantly during experiment either in male or female rat hearts. However, P-Cx43 as well as ratio of P to total Cx43 decreased significantly due to 10-min VF and 2-min VF in males only. In parallel, there was a significant increase of noP forms of Cx43 due to 10-min VF and 2-min VF in males only. Surprisingly, an enhancement of noP-Cx43 was detected at the moment of brief stop perfusion-induced cardioversion in both male and female rat hearts. It was associated with suppression of P-Cx43.


VF itself down-regulates Cx43 and this process is faster in male than female rat heart. While sudden global increase of un-phosphorylated form of Cx43 might be involved in cardioversion most likely due to temporal myocardial cell-to-cell uncoupling. This work was supported by VEGA 2/0046/12 grant.

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