Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

摘要

HCN channels underlie the depolarizing funny current (Isubf/sub) that contributes importantly to?cardiac pacemaking. Isubf/sub is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4suptg/wt/sup) to assess functional consequences of HCN4 overexpression-mediated Isubf/sub increase in cardiomyocytes to levels observed in human heart failure. HCN4suptg/wt/sup animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. Isubf/sub augmentation induces a diastolic Nasup+/sup influx shifting the Nasup+/sup/Casup2+/sup exchanger equilibrium towards 'reverse mode' leading to increased [Casup2+/sup]subi/sub. Changed Casup2+/sup homeostasis results in significantly higher systolic [Casup2+/sup]subi/sub transients and stimulates apoptosis. Pharmacological inhibition of Isubf/sub prevents the rise of [Casup2+/sup]subi/sub and protects from ventricular remodeling. Here we report that augmented myocardial Isubf/sub alters intracellular Casup2+/sup homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial Isubf/sub per se may constitute a therapeutic mechanism to prevent cardiomyopathy.