Abstract 20353: Serum and Glucocorticoid-Regulated Kinase 1 (SGK1) Activation Predisposes to Lethal Reperfusion Ventricular Arrhythmias while Inhibition Is Protective in a Mouse Model of Ischemia-Reperfusion
Background: Transgenic (TG) mice with cardiac-specific expression of constitutively-active SGK1 (SGK1-CA) have cardiac dysfunction, ventricular arrhythmias (VA), and increased persistent Na current INaL. Expression of dominant negative SGK1 (SGK1-DN) in the heart protects against progression to heart failure following pressure-overload. We tested the hypothesis that SGK1 activation may be deleterious, while inhibition may be beneficial in a mouse model of ischemia/reperfusion (I/R).
Methods: TG mice and age-matched wild-type (WT) littermates were subjected to 30 min. ischemia and either 24 hour (acute I/R) or 4 weeks reperfusion (chronic I/R). Heart rhythm was monitored acutely and by implanted recorders for 24 hours following I/R. Harvested hearts were analyzed for infarct size, area at risk and TUNEL positive cells.
Results: SGK1-CA TG mice subjected to I/R had an increase in mortality (8/10) compared with WT (7/29) or SGK1-DN mice (2/16), p =0.006. There was a trend towards increased PVCs in the SGK-CA TG (21 vs 5.7 in WT, p = 0.06) in the 12 hours prior to I/R. SGK1-CA mice had increased VA during ischemia (5/5 in TG vs 1/4 in WT) and lethal VA including polymorphic VT in the first 60 minutes of reperfusion (4/5 in TG vs 0/4 in WT, confidence level 91%). In contrast, SGK1-DN TG did not have increased mortality following I/R, but showed a decrease in infarct size compared with WT mice (infarct/area at risk 40± 12% in WT mice, 23 ± 12% in SGK1-DN mice, p=0.04). There was a corresponding decrease in apoptotic nuclei in the infarct and border zone (4.133% in WT versus 3% in SGK1-DN) suggesting a possible mechanism for cardioprotection. Compared to WT littermates, SGK1-DN mice subjected to chronic I/R had smaller increases in LV diastolic dimension (3.37 ± 0.17 cm in SGK1-DN vs 4.08 ± 0.26 cm in WT, n=3) and smaller decreases in fractional shortening (62 ± 2.5 % in SGK1-DN vs 43 ± 9% in WT) suggesting salutary effects on ventricular remodeling.
Conclusions: Chronic SGK1 activation increases the susceptibility to lethal VA during reperfusion, likely through an increase in APD prolongation and INaL. SGK1 inhibition in the heart decreases infarct size and cardiomyocyte apoptosis following I/R, and has a beneficial effect on ventricular remodeling in chronic I/R.
- © 2010 by American Heart Association, Inc.