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Cocaine induces apoptosis in fetal rat myocardial cells through the p38 mitogen-activated protein kinase and mitochondrial/cytochrome c pathways.
J Pharmacol Exp Ther. 2005 Jan; 312(1):112-9.JP

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 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 a time point of 15 min but reduced the extracellular signal-regulated kinase (ERK) activity at 5 and 15 min in FRMCs. The p38alpha 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 p38beta MAPK and mitogen-activated protein kinase kinase/ERK inhibitors SB 202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole] and PD98059 (2'-amino-3'-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, p38alpha 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, p38beta MAPK and ERK protect fetal myocardial cells against apoptosis.

Authors+Show Affiliations

Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15365088

Citation

Li, Guohu, et al. "Cocaine Induces Apoptosis in Fetal Rat Myocardial Cells Through the P38 Mitogen-activated Protein Kinase and Mitochondrial/cytochrome C Pathways." The Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 1, 2005, pp. 112-9.
Li G, Xiao Y, Zhang L. Cocaine induces apoptosis in fetal rat myocardial cells through the p38 mitogen-activated protein kinase and mitochondrial/cytochrome c pathways. J Pharmacol Exp Ther. 2005;312(1):112-9.
Li, G., Xiao, Y., & Zhang, L. (2005). Cocaine induces apoptosis in fetal rat myocardial cells through the p38 mitogen-activated protein kinase and mitochondrial/cytochrome c pathways. The Journal of Pharmacology and Experimental Therapeutics, 312(1), 112-9.
Li G, Xiao Y, Zhang L. Cocaine Induces Apoptosis in Fetal Rat Myocardial Cells Through the P38 Mitogen-activated Protein Kinase and Mitochondrial/cytochrome C Pathways. J Pharmacol Exp Ther. 2005;312(1):112-9. PubMed PMID: 15365088.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cocaine induces apoptosis in fetal rat myocardial cells through the p38 mitogen-activated protein kinase and mitochondrial/cytochrome c pathways. AU - Li,Guohu, AU - Xiao,Yuhui, AU - Zhang,Lubo, Y1 - 2004/09/13/ PY - 2004/9/15/pubmed PY - 2005/4/14/medline PY - 2004/9/15/entrez SP - 112 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 312 IS - 1 N2 - 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 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 a time point of 15 min but reduced the extracellular signal-regulated kinase (ERK) activity at 5 and 15 min in FRMCs. The p38alpha 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 p38beta MAPK and mitogen-activated protein kinase kinase/ERK inhibitors SB 202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole] and PD98059 (2'-amino-3'-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, p38alpha 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, p38beta MAPK and ERK protect fetal myocardial cells against apoptosis. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15365088/Cocaine_induces_apoptosis_in_fetal_rat_myocardial_cells_through_the_p38_mitogen_activated_protein_kinase_and_mitochondrial/cytochrome_c_pathways_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15365088 DB - PRIME DP - Unbound Medicine ER -