Abstract 3866: A Peptide Containing the Carboxy-Terminal Domain of Connexin43 Reduces Arrhythmias and Improves Cardiac Function after Myocardial Injury
Disease-associated remodeling of Cx43 gap junctions (GJ) has been linked to increased incidence of cardiac arrhythmias. We have previously reported that dynamic interaction between Cx43 and the actin-binding protein ZO-1 is an important determinant of GJ size and distribution in cardiomyocytes. As part of this work we developed a membrane-permeant peptide incorporating a carboxy-terminal (CT) domain of Cx43, designed to competitively inhibit the interaction between Cx43 and ZO-1. Based on its effects on gap junction remodeling in vitro, we hypothesized that this peptide would improve cardiac function after myocardial injury. We determined the effects of this inhibitory peptide on myocardial wound healing in a novel model of myocardial cryoinjury that produces non-transmural left ventricular injuries of reproducible size and geometry. After cryoinjury, the wounds were treated with adherent methylcellulose patches formulated to release the inhibitory peptide, a control peptide, or vehicle. Serial M-mode echocardiographic analyses indicated that relative to controls there was significant functional improvement in the inhibitory peptide treated hearts, and that this effect was most pronounced at 1-week post-cryoinjury (n=20). Immunohistochemical analysis of 1-week hearts indicated that there were significant and quantifiable decreases in lateralization and mislocalization of Cx43 in inhibitory peptide-treated hearts at injury border zones. Since Cx43 gap junction remodeling is associated with arrhythmia, we used programmed stimulation to determine whether inhibitory peptide-treatment was associated with inhibition of arrhythmogenicity following cryoinjury (n=22). In peptide-treated hearts, it was determined that the number of arrhythmias induced by premature pacing reduced significantly. We also found that the overall severity of the induced arrhythmias was dramatically attenuated relative to controls in injured hearts treated with the inhibitory peptide. These data indicate that peptides based on the CT of Cx43 have potential as novel therapeutic agents in sub-acute arrhythmias in patients who have recently suffered from a myocardial infarction.
This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).