Up-regulated Cx43 phosphorylation at Ser368 prolongs QRS duration in myocarditis

Prolongation of QRS duration in electrocardiogram is one of the risk factors for morbidity and mortality in many kinds of cardiac diseases. However, its molecular mechanism is unknown. In this study, utilizing experimental autoimmune myocarditis (EAM) as a disease model, we show that the prolongation of QRS duration is accompanied by elevated phosphorylation of connexin 43 (Cx43) at Ser368 (p^S368 Cx43). In cultured cells, inflammatory cytokine IL-1β activates p38 MAPK to up-regulate p^S368 Cx43 and impairs cell-to-cell communication. In isolated hearts of normal rats, perfusion of IL-1β not only increases p^S368 Cx43 but also impairs cell-to-cell communication and prolongs QRS duration. Furthermore, blockade of p38 MAPK down-regulates p^S368 Cx43, improves cell-to-cell communication and reduces QRS duration in EAM. These findings suggest that up-regulation of p^S368 Cx43 by IL-1β via p38 MAPK contributes to the prolongation of QRS duration and could be a therapeutic target for myocarditis-induced prolongation of QRS duration.