Arrhythmogenic?properties?of?dismantling?cadherin-mediated?adhesion?in?murine?hearts

Objective:??To?evaluate?the?arrhythmogenic?effects?of?dismantling?cadherin-mediated?adhesion?by?recombinant?mouse?aminopeptidase?N?(rmAPN)?in?murine?hearts.?Methods:?rmAPN?was?incubated?with?cultured?neonatal?rat?cardiomyocytes?as?well?as?being?infused?in?adult?mice.?The?cell-cell?connections?were?immunolabelled?and?ob-served?by?laser?confocal?microscopy.?Disruption?of?the?N-terminal?of?N-cadherin?(N-cad)?was?detected?by?western?blot?and?quantitative?immunofluorescence.?The?risk?of?inducible?ventricular?tachyarrhythmia?was?evaluated?in?mice?by?an?electrophysiological?study.?Results:?Disrupted?cell-cell?contact?was?observed?in?cultured?neonatal?rat?cardiomyocytes?in?response?to?30-40?ng/μL?rmAPN.?Loss?of?the?N-terminal?in?N-cad?and?altered?distribution?of?connexin?43?(Cx43)?were?observed?in?hearts?from?rmAPN-infused?mice.?In?addition,?a?reduction?of?phosphorylat-ed?Cx43?was?also?detected?concomitant?with?redistribution?of?Cx43.?Electrophysiological?studies?of?rmAPN-in-fused?mice?showed?prolonged?QRS?duration?and?increased?inducibility?of?ventricular?tachycardias.?Conclusion:?Disruption?of?N-cad?by?rmAPN?contributes?to?gap?junction?remodeling?and?may?elicit?arrhythmogenic?effects.?The?disorder?of?adherent?junctions?by?proteolytic?enzymes?may?play?an?important?role?in?arrhythmogenic?mechanisms?in?correlated?diseases.