The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is hypothesized to regulate ionic currents and intracellular Ca2+ ([Ca2+]i) homeostatic functions that are critical for normal cardiac contraction. Excessive CaMKII activity triggers arrhythmias and causes cardiac hypertrophy, so CaMKII is a candidate molecule for inhibitory therapies in diverse cardiovascular diseases. One important obstacle for unraveling the role of CaMKII in heart has been the lack of selective inhibitory agents that can chronically target CaMKII activity. Our laboratory recently developed a transgenic mouse model of chronic, cardiac-targeted CaMKII inhibition using a highly selective CaMKII inhibitory peptide. These mice have significantly reduced cardiac CaMKII activity, and will be used to test hypothesized CaMKII regulation of ionic currents and [Ca2+]i homeostatic functions in cardiac myocytes. Exercise testing, optical AV nodal conduction measurements, and echocardiographic assessment will all be used to link cellular effects of chronic CaMKII inhibition to physiologic consequences, using the following specific aims: 1. Measure cardiac CaMKII activity and define the functional consequences of targeted cardiac CaMKII inhibition in vivo. 2. Determine the effect of specific CaMKII inhibition on cardiac excitation-contraction coupling. 3. Determine the effect of specific CaMKII inhibition on L-type Ca2+ current, Na+/Ca2+ exchanger current, and the transient outward K+ current. 4. Measure functional and biochemical consequences of CaMKII-beta adrenergic signaling cross talk. Our preliminary in vivo data indicate that mice with cardiac CaMKII inhibition have incomplete functional compensation by up-regulation of beta adrenergic signaling, while cellular studies show these animals have significantly reduced L-type Ca2+ channel activity, and reduced sarcoplasmic reticulum (SR) Ca2+ content. These findings suggest that this new and innovative model will yield important information on hypothesized CaMKII regulation of cardiac cellular and in vivo physiologic functions.
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