Regulation of IK by PI3 Kinase/Akt Pathway in Cardiac Myocytes

Abstract

Abnormal regulation of the repolarization process in cardiac myocytes is related to the induction of certain arrhythmias and ventricular dysfunction. Regulation of the repolarizing delayed outward rectifier current (IK) can be modulated by inotropic and inotrophic hormones, such as IGF‐1. The aim of this work was to assess the regulation of IK by the cell‐survival pathway, IGF‐1/PI3 K/Akt, in freshly isolated neonatal rat ventricular myocytes, using patch‐clamp technique in whole‐cell configuration. Cells were stimulated from holding potential of ‐40mV, by 500msec, 10‐mV step voltages to +40mV. IGF‐1 reduced the functional density of IK from 4.1 ± 0.5 pA/pF to 2.6 ± 0.3 pA/pF. IGF‐1 effect was eliminated by the PI3 Kinase inhibitor, LY294002 (3μM). Adenoviral transfection of cardiocytes with a constitutively activated PI3 K, BD110, mimicked the IGF‐1 effect on IK (2.5 ± 0.4 pA/pF), which was abrogated by LY 294002. Similar to BD110, transfection of the cardiac myocytes with wild‐type Akt reduced IK (2.4 ± 0.3 pA/pF), which was completely reversed by LY 294002. We conclude that IK is negatively regulated by IGF‐1 through downstream activation of PI3 Kinase and Akt. Such a mechanism could play an anti‐arrhythmic role during cardiac events that are associated with the activation of the PI3 K/Akt signaling, such as cardiac hypertrophy.