Improving gap junction communication as an antiarrhythmic mechanism

Prof. Dr. Dhein, Stefan. Herzzentrum Leipzig Clinic for Cardiac Surgery, Struempellstr. 39, 04289 Leipzig, Germany.

Cardiomyocytes communicate via gap junction channels. These gap junction channels are constructed as dodecameric channels from protein subunits called connexin. The main cardiac connexin isoforms are Cx43 (ubiquitous), Cx40 (mostly in atrium and specific conduction system) and Cx45 (in early developmental states and between fibroblasts and cardiomyocytes). Gap junction channels allow the transfer of current and of small molecules.

Gap junction channels are regulated by a broad number of stimuli, which can either affect conductance or the number of channels. Ions like H+, Ca++, Na+ as well as ATP-loss, acylcarnitines among others can close the channels. Since these factors occur during cardiac ischemia, they lead to electrical isolation of the ischemic area. Uncoupling is involved in type II ventricular fibrillation (late ischemic VF) and in atrial fibrillation. Thus, improvement of gap junction intercellular communication (GJIC) might prevent from these arrhythmias. New developments in that field are antiarrhythmic peptides, such as AAP10 (Dhein et al., 1994, Grover & Dhein, 1998) which enhance GJIC. This effect of AAPs is mediated via PKCa-dependent phosphorylation of Cx43 (Weng et al, 2002). Functionally, AAP10 reduces inhomogeneities of the action potential duration. The effect is confined to areas of increased Cx-de-phosphorylation and thereby shows preference for ischemic tissue (Jozwiak & Dhein, 2008). AAP10 prevented from type 2 VF (Grover & Dhein, 2001). In human atrial cardiomyocytes, CO2 incubation leads to GJIC uncoupling, which can be completely prevented by AAP10 (50 nM) (Hagen et al., 2009). In addition, after previous CO2-uncoupling AAP10 reversed GJIC in human cardiomyocytes and lead to a complete normalisation despite the enduring presence of acidotic conditions. AAP10 preferentially affects Cx43 and Cx45, but not Cx40 (Hagen et al., 2009). The new agents open new pharmacological tools for prevention of ischemia-associated ventricular fibrillation.

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