Abstract 18907: Genetic Ablation of Voltage-Gated Potassium Channel β-subunit 2 Causes Distinct Physiological and Cardiac Alterations in Mice
Voltage-gated potassium channels (Kv) are important for cardiac function. Recent studies from our group showed dysregulation of Kv4.2 and 1.4 in diabetes or hyperoxia. The activity of Kvα is regulated by β-subunits and mutations in these subunits are associated with cardiovascular diseases. Recent report suggests that Kvβ2 (Kcnab2), a dominant β-subunit in the brain modulates inactivation rates of Kv1.4 currents and can promote the trafficking of Kv1.1 and 1.2 to the cell surface. The physiological and molecular roles of Kvβ2 in cardiac functioning are unknown. Therefore, in the current study we investigated the functional alterations and assessed the molecular changes in Kvβ2KO (KO) mouse hearts. Physical assessment of heart reveals significant cardiac atrophy in KO by measure of heart weight to tibia length ratio, WT: 7.44±0.31mg/mm vs KO: 6.23±0.15mg/mm (p<0.002). The shape and structure of KO mouse hearts are smaller than their littermate wild type (WT). Molecular evaluation shows significant (p≤0.05) elevation of atrophy markers such as pyruvate dehydrogenase lipoamide kinase isozyme 4, uncoupling protein 3, atrogin, insulin-like growth factor, phospholamban, calcineurin, and slow-twitch myosin heavy chain-7. Echocardiography showed significant reduction in end diastolic volume (EDV) in KO mice compared with WT (15% less in KO than WT, p<0.01). Action potentials recorded at room temperature from right ventricular myocytes showed that KO (n=18) had significantly slower action potential durations than WT (n=27) at APD20 (2.04±0.08ms vs. 1.78±0.06ms, p<0.025), APD50 (4.45±0.34ms vs. 3.64±0.24ms, p<0.05), and APD90 (24.30±2.56ms vs. 17.42±1.22ms, p=0.01) levels. Lead II ECG recordings from anesthetized WT and KO mice were unchanged. Western blotting revealed a significant elevation of Kvβ1.2 in right ventricle and Kv1.5 in left ventricle of KO hearts. Based on functional and pathological assessment the extent of atrophy in KO hearts along with biochemical and molecular mechanisms are reported for the first time in this study. In summary our study showed that genetic deletion of Kvβ2 cause distinct physiological and cardiac changes suggesting its importance in cardiac physiology.
- © 2013 by American Heart Association, Inc.