Apoptosis repressor with caspase domain inhibits cardiomyocyte apoptosis by
reducing K+ currents.
Ekhterae, Daryoush, Oleksandr Platoshyn, Shen Zhang, Carmelle V. Remillard, and
Jason X.-J. Yuan.
Department of Medicine, School of Medicine, University of California, San Diego,
California 92103
APStracts 10:0056C, 2003.
Cell shrinkage is an early prerequisite in programmed cell death, and cytoplasmic K+ is a
dominant cation that controls intracellular ion homeostasis and cell volume. Blockade of
K+ channels inhibits apoptotic cell shrinkage and attenuates apoptosis. We examined
whether apoptotic repressor with caspase recruitment domain (ARC), an antiapoptotic
protein, inhibits cardiomyocyte apoptosis by reducing K+ efflux through voltage-gated
K+ (Kv) channels. In heart-derived H9c2 cells, whole cell Kv currents (IK(V)) were
isolated by using Ca2+-free extracellular (bath) solution and including 5 mM ATP and 10
mM EGTA in the intracellular (pipette) solution. Extracellular application of 5 mM 4-
aminopyridine (4-AP), a blocker of Kv channels, reversibly reduced IK(V) by 50-60% in
H9c2 cells. The remaining currents during 4-AP treatment may be generated by K+
efflux through 4-AP-insensitive K+ channels. Overexpression of ARC in heart-derived
H9c2 cells significantly decreased IK(V), whereas treatment with staurosporine, a potent
apoptosis inducer, enhanced IK(V) in wild-type cells. The staurosporine-induced increase
in IK(V) was significantly suppressed and the staurosporine-mediated apoptosis was
markedly inhibited in cells overexpressing ARC compared with cells transfected with the
control neomycin vector. These results suggest that the antiapoptotic effect of ARC is, in
part, due to inhibition of Kv channels in cardiomyocytes.
Received 18 June 2002; accepted in final form 23 January 2003
APS Manuscript Number C279-2.
Article publication pending Am J Physiol Cell Physiol
ISSN 1080-4757 Copyright 2003 The American Physiological Society.
Published in APStracts on 25 March 2003