Received for publication June 30, 2004.
Revised September 8, 2004.
Accepted for publication September 13, 2004.

Cocaine induces apoptosis in fetal rat myocardial cells through the p38 MAPK and mitochondrial/cytochrome c pathways

Abstract

Cocaine induces apoptosis in fetal rat myocardial cells (FRMCs). However, the mechanisms are not clear. The present study examined the role of p38 MAPK and cytochrome c release in the cocaine-induced apoptosis in primary culture of FRMCs prepared from the fetal heart of 21-day gestational age. Cocaine induced time-dependent, concurrent increases in cytochrome c release and activities of caspase-9 and caspase-3, which preceded apoptosis. Caspase-8 was not activated. In accordance, cyclosporin A and the inhibitors of caspase-9 and caspase-3 inhibited cocaine-induced caspase activation and apoptosis. Cocaine stimulated a transient increase in the p38 MAPK activity at time point of 15 min, but reduced the ERK activity at 5 and 15 min in FRMCs. The p38 MAPK inhibitor SB203580 inhibited cocaine-induced activation of caspases and apoptosis. In contrast, the p38 MAPK and MEK/ERK inhibitors SB202190 and PD98059, respectively, increased apoptosis in the absence of cocaine, and potentiated cocaine-induced apoptosis. Consistent with its inhibition of apoptosis, SB203580 inhibited cocaine-induced cytochrome c release and activation of caspase-9 and caspase-3. In addition, cocaine induced a decrease in Bcl-2 protein levels, with no effect on Bax levels. The cocaine-mediated reduction of Bcl-2 levels was not affected with SB203580 and the caspase inhibitors. The results suggest that in FRMCs, p38 MAPK plays an important role in the cocaine-induced apoptosis by promoting cytochrome c release, downstream or independent of Bcl-2 protein-mediated regulation. In contrast, p38 MAPK and ERK protect fetal myocardial cells against apoptosis.

Key words: ERK, apoptosis, cocaine, heart, mitochondria, p38 MAPK

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