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• W1986529465 abstract "Caveolae are discrete microdomains in cardiomyocytes that localize many ion channels and signaling proteins to enable compartmentalized regulation of cardiac signaling and physiology. Caveolin-3 (Cav-3) is a muscle specific scaffolding protein integral to caveolae in cardiomyocytes. Previous studies have indicated reduced Cav-3 expression and caveolae in cardiac hypertrophy and heart failure. These forms of heart disease are associated with prolonged cardiac repolarization, which puts patients at an increased risk for arrhythmias and sudden cardiac death. Furthermore, mutations in the CAV3 gene are linked to congenital Long QT syndrome (LQTS9). We hypothesize that caveolae provide integrated regulation of cardiac repolarization by controlling the density and functional properties of multiple classes of ion channels. To determine the impact of Cav-3 expression levels on cardiac repolarization we generated a cardiac-specific conditional Cav-3 knockout (Cav-3−/−) mouse. Western blot and transmission electron microscopy analysis demonstrated reduced expression of Cav-3 (88%) and the absence of caveolae respectively in the ventricular myocytes of Cav-3−/− mice compared to wild type (WT) mice. The Cav-3−/− mice demonstrate a significant increase in the telemetry ECG QT interval. Action potentials durations (APD) measured in ventricular myocytes from Cav-3−/− mice were significantly increased, APD50:30±9 ms and APD90:87±15 ms compared to littermate WT mice (APD50:9±2 ms; APD90:18±6 ms). Furthermore, whole-cell voltage clamp experiments in isolated ventricular myocytes from the Cav-3−/− mice demonstrated changes in a number of ionic currents including reduced peak Ito (19.6±2.4 pA/pF compared to 11±1.4 pA/pF in WT cells) and significantly delayed inactivation of ICa,L. We conclude that loss of Cav-3 expression impacts the function of multiple types of ion channels causing delayed cardiac repolarization and so may be integrally linked to arrhythmias and sudden cardiac death." @default.
• W1986529465 created "2016-06-24" @default.
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• W1986529465 date "2013-01-01" @default.
• W1986529465 modified "2023-09-28" @default.
• W1986529465 title "Loss of Caveolin-3 Results in QtC Prolongation and Causes Delayed Cardiac Repolarization in a Cardiac-Specific Conditional CAV-3 Knockout Mouse Model" @default.
• W1986529465 doi "https://doi.org/10.1016/j.bpj.2012.11.1183" @default.
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