Modulation of Potassium Currents by MAPK and PI 3K during Eccentric Cardiac Hypertrophy

Abstract

The activities of the inward rectifier K+ channel (IK1), responsible for the maintenance of the resting potential, and the outward rectifier K+ channel (IK), controlling the repolarization of the action potential, are crucial for myocardial contraction; which is altered during eccentric cardiac hypertrophy. Angiotensin II (ANG II) has been shown to be a key element in the development of cardiac hypertrophy. The aim was to study the intracellular regulation of IK1 and IK by ANG II in sham and aortocaval shunt-induced eccentric cardiac hypertrophy in the adult rat. Whole-cell patch-clamp was conducted on freshly isolated ventricular myocytes from sham and shunt rat hearts in the presence of 1μM of either of the specific inhibitors for p38 (SB203580), ERK1/2 (PD98059) and PI 3K (LY294002). In the sham, the effect of ANG II on IK1 was completely abrogated upon ERK1/ERK2 inhibition, and it was reduced by more than 50% when p38 kinase activity was inhibited. In the hypertrophied myocytes, ANG II-induced effects on IK1 were completely prevented by either ERK1/ERK2 or Akt inhibition; whereas p38 inhibition reversed ANG II inhibition of IK1 into activation. On the other hand, neither p38 nor Akt inhibition affected the ANG II-induced decrement in IK; but it was prevented by ERK1/ERK2 inhibition in the sham. However, ANG II effect on IK was abrogated by ERK1/2, p38 or Akt inhibition in the hypertrophied ventricular myocytes. Thus, ANG II induced reductions in IK and IK1 seem to be mainly ERK1/2-dependent in the sham; but ERK1/2- and Akt-dependent in the shunt, in addition to p38 for IK. This project was supported by NIH/NIGMS SCORE S06GM08016-32