Abstract 20389: Serum- and Glucocorticoid-Regulated Kinase 1 Contributes to Adverse Electrical Remodeling by Regulating Cardiac Na+ Channels
Introduction: Altered cardiac Na+ channel function and increased persistent Na+ current (INaL) are associated with ventricular tachycardia in inherited and acquired heart disease. The mechanistic basis of the increased INaL in acquired heart disease remains incompletely understood. We investigated the role of serum- and glucocorticoid-regulated kinase-1 (SGK1), a serine-threonine kinase that modulates channel function in other systems.
Methods: Transgenic (TG) mice with cardiac-specific expression of constitutively-active (SGK1-CA) or dominant-negative SGK1 (SGK1-DN) were generated, and compared with wild-type (WT) littermates using echocardiography, invasive hemodynamics and electrophysiology studies. Adult cardiomyocytes (CMs) from SGK1-CA or WT mice were subjected to whole-cell patch clamp. Cardiac function, histology, and protein expression were investigated in TG and WT mice subjected to transverse aortic constriction (TAC) for 7 weeks.
Results: phospho-SGK1 was increased in human patients with dilated cardiomyopathy (2.3 ± 0.85 fold, p<0.005) compared to control hearts. While SGK1-DN TGs had normal cardiac structure and function, SGK1 activation led to increased mortality, decreased fractional shortening p<0.001, n=9–13; decreased dP/dtmax, dP/dtmin, PRSW, p<0.05, n=4 and ventricular arrhythmias (inducible VT 50% in SGK1-CA vs 0% in WT and SGK1-DN, n=4). SGK1 activation altered the distribution, phosphorylation, and association of the cardiac sodium channel Nav 1.5, with the ubiquitin ligase Nedd 4–2, recapitulating changes seen in models of heart failure. SGK1-CA TG CMs showed action potential duration (APD) prolongation, increased Na+-current (INa) density and ‘window’ current, as well as increased INaL and after-depolarizations. Pharmacological inhibition of INaL normalized APD and reduced the frequency of after-depolarizations. SGK-DN TG animals subjected to TAC were protected from heart failure and fibrosis, and had abrogation of the biochemical changes in Nav 1.5 seen in WT-TAC mice.
Conclusion: SGK1 may provide a mechanistic link between acquired heart disease and arrhythmia through altered Na+ channel function and increased INaL, and may constitute a potential therapeutic target in these conditions.
- © 2010 by American Heart Association, Inc.