Cocaine Induces Apoptosis in Fetal Rat Myocardial Cells through the p38 Mitogen-Activated Protein Kinase and Mitochondrial/CytochromecPathways

Abstract

Cocaine induces apoptosis in fetal rat myocardial cells (FRMCs). However, the mechanisms are not clear. The present study examined the role of p38 mitogen-activated protein kinase (MAPK) and cytochrome c release in the cocaine-induced apoptosis in primary culture of FRMCs prepared from the fetal heart of gestational age of 21 days. Cocaine induced timedependent, 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 cocaineinduced caspase activation and apoptosis. Cocaine stimulated a transient increase in the p38 MAPK activity at a time point of 15 min but reduced the extracellular signal-regulated kinase (ERK) activity at 5 and 15 min in FRMCs. The p38␣ MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] inhibited cocaine-induced activation of caspases and apoptosis. In contrast, the p38␤ MAPK and mitogen-activated protein kinase kinase/ERK inhibitors SB 202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole] and PD98059 (2Ј-amino-3Ј-methoxyflavone), 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.Cocaine abuse among women of childbearing age is prevalent in the United States. A number of developmental disorders in human infants have been attributed to cocaine exposure in utero. These include decreased birth weight and head circumference, sudden infant death syndrome, systemic hypertension, and tachycardia (Handler et al., 1991;Silvestri et al., 1991). Cocaine can cross the placenta and accumulate in the fetus (Schenker et al., 1993). Our recent studies have demonstrated that maternal cocaine administration during pregnancy induces apoptosis in the fetal heart . Cocaine also directly induces an increase in apoptotic cell death in fetal rat myocardial cells (FRMCs) . However, the cellular and molecular mechanisms responsible for cocaine-induced cardiac myocyte apoptosis are presently not clear.Apoptotic cell death is characterized by the activation of a unique class of aspartate-specific proteases, i.e., caspases. Sequential activation of caspases results in cleavage of substrate proteins and breakdown of DNA molecules. It has been well documented that the caspase cascade involved in apoptosis includes...

Characterization of cocaine-elicited cell vacuolation: the involvement of calcium/calmodulin in organelle deregulation

“…Cocaine-elicited apoptosis has been observed in rat fetal locus coeruleus neurons, myocardial and vascular smooth muscle cells, mouse hepatocytes, and human epithelial cells of nasal mucosa [55][56][57][58][59]. For example, in fetal rat myocardial cells, p38alpha mitogen-activated protein kinase (MAPK) plays an important role in the cocaine-induced apoptosis by promoting cytochrome c release [58]. It would then be of interest to apply MAPK inhibitors to observe if cocaine-induced vacuolation could be blocked and apoptosis be inhibited.…”

“…It has been reported that cocaine can induce cell death by either apoptotic or necrotic pathway [55][56][57][58][59][60][61][62][63]. Cocaine-elicited apoptosis has been observed in rat fetal locus coeruleus neurons, myocardial and vascular smooth muscle cells, mouse hepatocytes, and human epithelial cells of nasal mucosa [55][56][57][58][59]. For example, in fetal rat myocardial cells, p38alpha mitogen-activated protein kinase (MAPK) plays an important role in the cocaine-induced apoptosis by promoting cytochrome c release [58].…”

Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rats

“…Mitogen activated protein (MAP) kinases are a family of protein kinases associated with genes encoding stress, apoptotic response factors which determines the fate of the cardiomyoctes to undergo either survival or death in the myocardium [13].…”

An intriguing association between dental and mental pathology in addicted and control subjects: a cross-sectional survey

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