Cross-talk between MAPKs and PI-3K pathways alters the functional density of I(K) channels in hypertrophied hearts

Department of Physiology & Biophysics, College of Medicine, Howard University, Washington DC 20059, USA.
Ethnicity & disease (Impact Factor: 1). 03/2010; 20(1 Suppl 1):S1-219-24.
Source: PubMed


Mitogen activated protein kinases (MAPK), such as ERK1/2 and p38 MAPK and phosphatidylinositol-3 phosphate kinase (PI-3K) play a major role in the development of cardiac hypertrophy. Recently, we have shown their crucial role in the regulation of the myocardial function through their effects on crucial ion channels. It is the focus of this study to resolve the interaction between these pathways and its implication on the function of the normal and hypertrophied cardiomyocytes. To that end, we created arteriovenous fistula in the adult rat that developed volume-overload eccentric cardiac hypertrophy over a 3-week period. We measured the relative activity of ERK1/2, p38 MAPKs and Akt through western blot analysis and assessed the functional density of the outward rectifier potassium current (I(K)) using the patch-clamp technique. The results showed a mutual negative autoregulation between ERK1/2 and p38 in normal cardiomyocytes, which disappears during cardiac hypertrophy. In addition, PI-3K seems to assume a greater role in mediating IGF-1 effects on the MAPKs during cardiac hypertrophy. This was also relevant to I(K) functional density which was reduced by activation of both MAPKs and Akt by angiotensin II (ANG II) and insulin-like growth factor-1 (IGF-1), respectively; however, this reduction was reversed by inhibition of PI-3K alone in hypertrophied myocytes but not in normal ones. This raises an important implication relative to the role of IGF-1-dependent activation of PI-3K, which may translate into a differential prognostic for cardiac hypertrophy among ethnic groups. This is true in African Americans, having higher circulating IGF-1 levels, and especially true for the athletes among them.

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    • "We did not look for or observe any significant changes in the size of the neonatal cardiac myocytes that we studied. These normal neonatal cardiac myocytes were used as a model to determine whether the decrements in IK and IK1 density, which we previously observed in eccentrically hypertrophied adult rat cardiac myocytes and not in normal adult rat cardiac myocytes exposed to IGF-1 [8, 23] were effects inherent or specific to such hypertrophied cardiac myocytes. The results of the present study, demonstrating decreased IK and IK1 density in normal neonatal cardiac myocytes, suggest that similar effects could be elicited from not only eccentrically hypertophied adult rat cardiomyocytes, but also from normal neonatal rat cardiomyocytes treated with, or exposed to, IGF-1. "
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