Recent evidence shows that the auxiliary subunit KChIP2, which assembles with pore-forming
Kv4-subunits, represents a new potential regulator of the cardiac calcium-independent
transient outward potassium current (I(to)) 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 using a combination of molecular,
biochemical and gene targeting approaches. KChIP2 overexpression through gene transfer
of Ad.KChIP2 in neonatal cardiomyocytes resulted in a significant increase in I(to)-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.beta-gal-transduced
hearts, KChIP2 significantly attenuated the developed left ventricular hypertrophy,
robustly increased I(to) densities, shortened action potential duration, and significantly
altered myocyte mechanics by shortening contraction amplitudes and maximal rates of
contraction and relaxation velocities and decreasing Ca(2+) transients. Interestingly,
blocking I(to) with 4-aminopyridine in KChIP2-overexpressing adult cardiomyocytes
significantly increased the Ca(2+) transients to control levels. One-day-old rat pups
intracardially transduced with KChIP2 for two months then subjected to aortic banding
for 6-8 weeks (to induce hypertrophy) showed similar echocardiographic, electrical
and mechanical remodeling parameters. In addition, in cultured adult cardiomyocytes,
KChIP2 overexpression increased the expression of Ca(2+)-ATPase (SERCA2a) and sodium
calcium exchanger but had no effect on ryanodine receptor 2 or phospholamban expression.
In neonatal myocytes, KChIP2 notably reversed Ang II-induced hypertrophic changes
in protein synthesis and MAP-kinase activation. It also significantly decreased calcineurin
expression, NFATc1 expression and nuclear translocation and its downstream target,
MCiP1.4. Altogether, these data show that KChIP2 can attenuate cardiac hypertrophy
possibly through modulation of intracellular calcium concentration and calcineurin/NFAT
pathway.
(c) 2009. Published by Elsevier Ltd. All rights reserved.