Abstract 2808: SGK1 Activation in Cardiomyocytes Leads to Alteration of SCN5a Function, Electrical Remodeling and Left Ventricular Dysfunction
Background: We have previously shown that the serum and glucocorticoid-responsive kinase-1 (SGK1) is activated in animal models of heart failure (HF) as well as in human HF. In neonatal ventricular myocytes (VM) in vitro, SGK1 regulates voltage-gated sodium channel SCN5a in multiple ways. However, the in vivo effects of SGK1 in the heart are unknown.
Methods and Results:
Transgenic mice with cardiac specific over-expression of a constitutively active SGK1 (SGK-CA) or dominant negative SGK1 (SGK-DN) were created. SGK-CA TG mice exhibited increased mortality in two transgenic lines, and cardiac hypertrophy, fibrosis, and inducible ventricular arrhythmias in a third line with lower expression of the transgene.
SGK-CA Tg mice had premature development of ventricular dilatation and dysfunction compared with wild-type (WT) littermates in the TAC model of hypertrophy and HF.
QRT-PCR did not show differences in transcripts for voltage-gated K-channels or SCN5a, but immunoblotting revealed increased SCN5a protein (1.27 fold increase) and Na-Ca exchanger (1.59 fold increase).
Sucrose gradient fractionation showed redistribution of SCN5a from the lipid raft to the heavy membrane fraction.
Patch-clamp recording of VMs from SGK-CA TG mice showed prolonged action potential duration and spontaneous EADs. Inward sodium current density was increased in Tg VMs (−61 pA/pF vs −52 pA/pF) and the steady state activation curve for the sodium channel was shifted to more hyperpolarized potentials (V1/2 −69 mV vs −58 mV in WT). There was also a marked increase in the late sodium current in the TG VMs compared with WT CMs.
SGK-DN TG mice had normal cardiac structure and function at baseline but had significantly less left ventricular dilatation and dysfunction 6 weeks after TAC (n=8 in each group, p<0.05).
SGK1 inhibition appeared to prevent TAC-induced redistribution of SCN5a.
Conclusions: Chronic SGK1 activation in the heart results in electrical remodeling and cardiac dysfunction. Conversely, chronic inhibition of SGK1 mitigates TAC-induced ventricular dilatation and dysfunction. SGK1 may play a critical role in the transition from hypertrophy to HF, and inhibition of SGK1 warrants exploration as a therapeutic target in HF and electrical remodeling.