Abstract 1505: The Serum and Glucocorticoid Responsive Kinase-1 (SGK-1) is Activated in Human Cardiomyopathy and Mediates Hypertrophy-associated Electrical Remodeling and Left Ventricular Dysfunction
Background: We have previously shown that SGK-1 is upregulated by hypertrophic signals and mediates hypertrophy-induced changes in the voltage-gated sodium channel SCN5a. However, the in vivo effects of SGK-1 in the heart are unknown.
Methods: Protein from heart samples from patients with dilated cardiomyopathy (DCM), hypertensive heart disease (HHD) or controls were subjected to western blotting. Transgenic mice (Tg) expressing constitutively-active (CA) or dominant negative (DN) SGK-1 in the heart were analyzed by cardiac histochemistry, biochemistry, and integrative cardiac physiology. The effects of transverse aortic constriction (TAC) were examined in the SGK-DN mice.
Results: phospho-SGK-1 was markedly increased in DCM hearts (p<0.05), with less marked increase in HHD. There was a corresponding increase in Foxo-3A-phospho-serine (318), a specific target of SGK-1. SGK-CA expression in the mouse heart resulted in premature death in two transgenic lines. A third line with lower expression manifested cardiac hypertrophy, fibrosis, and inducible ventricular arrhythmias. Cardiomyocytes isolated from this line showed an increase in calcium influx (peak to rest ratio 0.28 in Tg, 0.17 in WT, p<0.0001). Immunoblotting revealed increased expression of the cardiac voltage-gated sodium channel SCN5a (1.27 fold increase), Na-Ca exchanger (1.59 fold increase), but not L-type calcium channel. Sucrose gradient fractionation showed redistribution of SCN5a from the lipid raft to the heavy membrane fraction, similar to hypertrophy-induced changes in SCN5a protein. SGK-DN transgenic mice had normal cardiac structure and function at baseline but reduced SCN5a expression. TAC induced hypertrophy in SGK-DN mice and wild-type littermates but SGK-DN had significantly less left ventricular dilatation and dysfunction 6 weeks after TAC (n=4 in each group, p<0.05).
Conclusions: SGK-1 is activated in human heart disease. Expression of SGK-CA in the heart results in electrical remodeling and cardiac dysfunction. Chronic inhibition of SGK-1 mitigates TAC-induced ventricular dilatation and dysfunction. Inhibition of SGK-1 warrants further exploration as a therapeutic target in heart failure and electrical remodeling.