Abstract 3584: Non-genomic and Protective Effects of Aldosterone on Cardiomyocytes Through a Transient Activation of Insulin Signaling
Aldosterone plays a pivotal role in the pathogenesis of heart failure (HF). Aldosterone antagonists inhibit the genomic action of aldosterone and express favorable results in the treatment of HF. However, less is known about the physiological actions of aldosterone. We hypothesized that aldosterone would have unknown protective effects on somatic cells mainly via its various non-genomic actions including glucose metabolism. To investigate the possible direct effects of aldosterone on cardiomyocytes and examine the implication of insulin signaling, neonatal rat cardiomyocytes (NRCMs) were stimulated with either short or long time exposure to aldosterone. Phosphorylation of Akt (Ser473) and its downstream effector, glycogen synthase kinase-3 (GSK-3β) (Ser 9) were substantially increased with a long time (24-hour) stimulation of aldosterone. This would be an unfavorable reaction since we have previously reported that chronic cardiac Akt activation leads to insulin resistance via negative feedback inhibition of its upstream effectors in human HF. Spironolactone reduced these phosphorylations by suppressing the genomic action of aldosterone. Intriguingly, we found that aldosterone transiently increased phosphorylation of Akt and GSK-3β within 10 minutes and subsequently suppressed these phosphorylations. These data suggest that, in cardiomyocytes, aldosterone is involved in insulin signaling with forming biphasic reaction. To understand the significance of this rapid action of aldosterone on cell viability, NRCMs were exposed to serum-deprivation with hyperglycemic condition. Surprisingly, a short term stimulation of aldosterone for 5–20 minutes rescued serum-deprivation induced damage in NRCMs (cell viability, % of control; 70.9±1.4% vs 37.2±3.3%, with or without aldosterone, respectively, n=6, p<0.02). In conclusion, aldosterone has favorable effects on cardiomyocytes partly by activating insulin signaling via non-genomic manner, while superfluous activity of aldosterone provides detrimental results through its genomic action. The present study also hints at the possibility of improvement in glucose metabolism by using indistinct mechanisms deeply involved in the non-genomic action of aldosterone.