Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Abstract

The potassium channels IK and IK1, responsible for the action potential repolarization and resting potential respectively, are altered during cardiac hypertrophy. The activation of insulin-like growth factor-I (IGF-I) during hypertrophy may affect channel activity. The aim was to examine the modulatory effects of IGF-I on IK and IK1 through mitogenactivated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways during hypertrophy. With the use of specific inhibitors for ERK1/2 (PD98059), p38 MAPK (SB203580) and PI3K/Akt (LY294002), Western blot and whole cell patch-clamp were conducted on sham and aorto-caval shunt-induced hypertrophy adult rat myocytes. Basal activation levels of MAPKs and Akt were increased during hypertrophy. Acute IGF-I (10 Ϫ8 M) enhanced basal activation levels of these kinases in normal hearts but only those of Akt in hypertrophied ones. IK and IK1 activities were lowered by IGF-I. Inhibition of ERK1/2, p38 MAPK, or Akt reduced basal IK activity by 70, 32, or 50%, respectively, in normal cardiomyocytes vs. 53, 34, or 52% in hypertrophied ones. However, basal activity of IK1 was reduced by 45, 48, or 45% in the former vs. 63, 43, or 24% in the latter. The inhibition of either MAPKs or Akt alleviated IGF-I effects on IK and IK1. We conclude that basal IK and IK1 are positively maintained by steady-state Akt and ERK activities.

Role of Apoptosis Signal-Regulating Kinase-1-c-Jun NH2-Terminal Kinase-p38 Signaling in Voltage-Gated K+Channel Remodeling of the Failing Heart: Regulation by Thioredoxin

“…Thus, we examined the electrophysiological role of insulin-like growth factor-1 (IGF-1) in the present study since this growth factor has been shown to exert significant antioxidant and antiapoptotic effects on the myocardium (18,36,39,44). As shown in Figure 3A, 10 nM IGF-1 for 4-5 h upregulated I to density in myocytes from MI hearts (filled squares) to a similar extent as JNK=p38 inhibitors.…”

“…3). It is possible that the lack of Kv channel remodeling in sham hearts by IGF-1 is related to unique cellular responses to acute versus sustained activation of ASK1-JNK-p38 signaling (12,18,39,40). It is also possible that distinct isoforms of JNK or p38 (26,31,34) are involved in Kv channel downregulation that are activated by pathogenic (e.g., angiotensin II and endothelin) but not physiologic (e.g., IGF-1) stimuli.…”

Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: Therapeutic perspectives

“…In addition, ERK1/2 can phosphorylate and modulate the activity of Na + /H + exchanger 1 (NHE-1), which is indirectly involved in Ca 2+ regulation in the heart (Moor and Fliegel, 1999). Inhibition of ERK1/2 also significantly reduced the K + channels ( I K and I K1 ) activity in hypertrophied adult cardiomyocytes (Teos et al, 2008). …”

Control of Cardiac Repolarization by Phosphoinositide 3-Kinase Signaling to Ion Channels

“…Acute treatment of rat ventricular myocytes with IGF-1, induction of volume-overload cardiac hypertrophy (which is associated with increased IGF-1 signaling and Akt activation) or adenoviral expression of Akt or constitutively active PI3K in rat neonatal cardiomyocytes were all reported to decrease the delayed rectifier current I K and the inward rectifier I K1 . 76, 77 On the other hand, repolarizing potassium currents in ventricular myocytes were upregulated in two models of physiological hypertrophy, one produced by cardiac-specific expression of constitutively active p110α and the other by swim training. 78 Protein and/or mRNA expression of numerous potassium channel subunits was also increased (Fig.…”