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Vol. 292, Issue 1, 8-14, January 2000
Center for Perinatal Biology, Department of Pharmacology and
Physiology, Loma Linda University School of Medicine, Loma Linda,
California
In the present study, we examined the direct cytotoxic effects of
cocaine on fetal cardiac myocytes. Cocaine treatment of cultured fetal
rat (21 days) myocardial cells (FRMCs) induced a time- and
concentration-dependent increase in apoptotic cells in FRMCs. Cocaine
induced surface exposure of phosphatidylserine in FRMCs at 12-h
treatment and increased apoptotic cells up to 96 h. Corresponding
DNA fragmentation induced by cocaine in these cells was demonstrated in
situ by terminal deoxynucleotidyl transferase biotin-dUTP nick end
labeling assay and by electrophoresis of labeled DNA fragments, showing
the characteristic apoptotic ladders. The
pD2 and maximum increase of cocaine-induced
apoptosis in FRMCs were 4.3 and 3.2-fold, respectively. Both caspase-9
and caspase-3 inhibitors (Z-LEHD-FMK and Ac-DEVD-CHO,
respectively) blocked cocaine-induced apoptosis. In addition,
cyclosporin A inhibited cocaine-induced apoptosis in a
concentration-dependent manner with an IC50 value of 0.1 µM. The maximum of 86% inhibition was obtained with 3 µM
cyclosporin A. Cocaine induced the release of cytochrome
c from the mitochondria and increased its levels in the
cytosol by 3.1-fold. In accordance, the level of cytochrome c in the mitochondria fraction decreased by ~60%.
Cocaine-induced translocation of cytochrome c was
inhibited by cyclosporin A. The results indicate that cocaine has a
direct cytotoxic effect on fetal cardiomyocytes by inducing apoptosis
in the cells. Furthermore, the release of cytochrome c
from the mitochondria and its subsequent activation of caspase-9 and
caspase-3 play a key role in cocaine-induced apoptosis.
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