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1 Department of Medicine, University of California, San Diego, San Diego, CA, USA
* To whom correspondence should be addressed. E-mail: xiyuan{at}ucsd.edu.
Cell shrinkage is an early prerequisite in the programmed cell death and cytoplasmic K+ is a dominant cation that controls intracellular ion homeostasis and cell volume. Blockade of K+ channels inhibits the apoptotic cell shrinkage and attenuates apoptosis. We examined whether ARC (apoptotic repressor with caspase recruitment domain), an anti-apoptotic 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 in comparison 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.
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