Abstract 3204: KChIP2 Targets Cardiac Hypertrophy Through Regulation of Action Potential Duration and Intracellular Calcium Cycling
Down-regulation of the cardiac calcium-independent transient outward potassium current (Ito) density is one of the most consistent findings in electrophysiological remodeling observed in humans and animal models of hypertrophy and failure. Recent evidence shows that the auxiliary subunit KChIP2, which assembles with pore-forming Kv4-subunits, may represent a new potential regulator of Ito density. In hypertrophy and heart failure, KChIP2 expression has been found to be significantly decreased. Our aim was to examine the role of KChIP2 in cardiac hypertrophy and the effect of restoring its expression on electrical remodeling and cardiac mechanical function. KChIP2 overexpression through gene transfer of Ad.KChIP2 in neonatal cardiomyocytes resulted in a significant increase in Ito-channel forming Kv4.2 and Kv4.3 protein levels. In vivo gene transfer of KChIP2 in aortic banded adult rats showed that, compared to sham-operated or Ad. β-gal-transduced hearts, KChIP2 has noticeably increased the expression of Kv4.2 and Kv4.3 protein, significantly attenuated the developed left ventricular hypertrophy, robustly increased Ito densities, markedly shortened action potential duration, and significantly altered myocyte mechanics by shortening contraction amplitudes and maximal rates of contraction and relaxation velocities and decreasing Ca2+ transients. In addition, in cultured adult cardiomyocytes, KChIP2 overexpression significantly increased the expression of SERCA2a and sodium calcium exchanger but had no effect on ryanodine receptor 2 or phospholamban expression. Moreover, in neonatal myocytes KChIP2 reversed AngII-induced hypertrophic changes in protein synthesis and MAP-kinase activation, and significantly decreased calcineurin and NFATc1 expression. Our data demonstrate that normalization of KChIP2 expression abrogates the hypertrophic response induced by pressure overload in hypertrophic hearts in vivo and by Ang II in cultured myocytes in vitro. KChIP2 can target cardiac hypertrophy by interfering with the calcineurin/NFAT pathway through a Ca2+-sensitive signaling system involving
regulation of Action Potential Duration, and
modulation of Ca2+ cycling proteins to alter intracellular Ca2+ content.