Abstract 2358: Loss of Integrin Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice
Background: Integrin-linked kinase (ILK) is a serine/threonine protein kinase with roles in signaling and molecular scaffolding of integrin-linked cell adhesion complexes. ILK mutation causes severe cardiomyopathy in man. Here, we analyzed the cellular and arrhythmic phenotype of ILK knock-out (KO) mice, with the use of a CRE-lox cardiac targeting system.
Methods: Adult mice expressing the cardiac mckCRE transgene and 2 loxP1-flanked ILK alleles (mckCRE ILKfl/fl -KO mice) were compared to littermate controls (CTLs). Cardiac performance was evaluated by echocardiography. ECG recording and intracardiac programmed stimulation (IPS) were used to investigate electrophysiology and arrhythmogenesis. Intercalated disk proteins were assessed by immunofluorescent analysis.
Results: Echocardiography showed decreased fractional shortening and cardiac output in KO mice vs CTLs (23.0±2.7 vs 38.8±2.3 %; 12±1 vs 14±1 ml/min respectively, p<0.01 for each). KO mice had increased QRS duration (16.2±1.5 ms vs 12.6±0.5* ms, *p<0.05) and QTc interval (63±3 vs 46±2* ms) vs CTLs. Telemetry revealed increases in the prevalence of ventricular extrasystoles (5/6 mice) and spontaneous ventricular tachycardia (VT, 1/6) in KO mice vs CTLs (0/5* mice). IPS induced VT in 6/7 KO mice vs 0/8 CTLs (p<0.01). Immunofluorescence showed loss and lateralization of connexin43 and plakoglobin (figure⇓), features associated with arrhythmogenic right ventricular cardiomyopathy (ARVC).
Conclusion: Loss of ILK produces an arrhythmogenic cardiomyopathic phenotype with features of ARVC, indicating that this molecular scaffold is important for maintaining cardiac cellular coupling integrity.