Abstract 11062: The δC Isoform of Ca 2+ /Calmodulin-Dependent Protein Kinase II (camk2) Regulates Cardiac Metabolic Substrate Switching in Mice

Abstract

Introduction: Ca 2+ /calmodulin-dependent protein kinase II (CaMK2) is a recognized driver of pathological cardiac remodeling and heart failure, but its role in the metabolic reprogramming of heart failure remains unclear, as do the molecular processes that trigger this pathologic switch. Hypothesis: Myocardial CaMKIIδ drives the pathological remodeling of cardiac metabolic substrate preference. Methods and Results: Adeno-associated viral (ssAAV9) overexpression of constitutively-active cytosolic (CaMK2δC) and nuclear (CaMK2δB) CaMK2δ isoforms, as well as the catalytic PKA subunit (PKAca), were created under the control of the cardiac troponin-T promoter and introduced via tail-vein injection into 12-week old mice (1 x 10 12 v.g., n = 5). In vivo metabolic phenotyping via 18-fluorodeoxyglucose ( 18 FDG)-based positron emission tomography (PET) revealed a 3.4-fold (P = 0.02) higher glucose uptake among mice receiving ssAAV9-TnnT-CaMK2δC commensurate with cardiac CaMK2δC expression. In contrast, no differences were seen in glucose uptake following AAV overexpression of cardiac CaMK2δB or PKAca relative to luciferase control vector. Echocardiography subsequently revealed a 14.6% decrease in left ventricular ejection fraction at 6 weeks following CaMK2δC overexpression (P = 0.047), whereas no changes were seen following CaMK2δB or PKAca overexpression in systolic or diastolic cardiac parameters. Conversely, transcriptomic analysis of hearts from mice lacking cardiac CaMK2δC expression revealed disproportionate up-regulation of fatty acid oxidative genes (P < 0.001). Conclusion: Taken together, these preliminary findings implicate CaMK2δC as a crucial regulator of the cardiac metabolic reprogramming that likely precedes the hemodynamic manifestations of cardiac dysfunction in heart failure.