Abstract P3146: Cardiac Stress-induced Arrhythmias And Myocardial Infarction Via Specific Genetically Phosphodeleted Sites In Connexin 43 Channels

Abstract

Connexin 43 (Cx43) gap junction remodeling is observed in various cardiac pathologies and is linked with arrhythmogenesis, myocardial infarction, and sudden death. Here, we aim to characterize the contribution of Cx43 phosphorylation toward mislocalization at the intercalated disc. For this, we used two genetically phospho-deleted Cx43 knock-in mouse lines with serine residues replaced by alanine in the corresponding sites for phosphorylation via mitogen-activated protein kinase (MAPK) (S255/262/279/282A; Cx43MK4) or Ca 2+/ calmodulin protein kinase II (CaMKII) (S325A/S328A/S330A; Cx43S3A). Ca 2+ signaling, cardiac electrical signals, and arrhythmias were assessed via optical mapping and telemetry in wild type, Cx43MK4, and Cx43S3A mice. Upon basal conditions or isoproterenol stimulation, wild-type animals did not display arrhythmogenic behaviors. However, after isoproterenol treatment, Cx43S3A mice showed increased QTc and deadly arrhythmias compared to wild-type animals. Isoproterenol challenge only increased the number of single PVCs in Cx43MK4 mice when compared to wild-type. Isoproterenol also evoked myocardial infarction in Cx43S3A hearts, which is negligible in Cx43MK4 and wild-type mice. Interestingly, GAP19, a Cx43 hemichannel blocker, reduced lethal arrhythmias and myocardial infarction in Cx43S3A mice. Isoproterenol challenge induced an increase in arrhythmogenic Ca 2+ events in both Cx43S3A and Cx43MK4 hearts compared to wild-type mice. However, Cx43S3A also displayed prolonged Ca 2+ decay transients that were reduced in the presence of Gap19. Our results suggest that the absence of Cx43 phosphorylation by CaMKII leads to lateralization and opening of Cx43 hemichannels, and consequently severe arrhythmias and myocardial infarction. On the other hand, the absence of MAPK phosphorylation promotes mainly a reduction of Cx43 levels at the intercalated disc region that is only associated with mild arrhythmias.