Maternal cocaine administration during pregnancy induces apoptosis in fetal rat heart.
We have previously demonstrated that cocaine induces apoptosis in primary cultures of fetal rat cardiomyocytes. The current study was designed to determine whether cocaine administered to the mother during pregnancy induced apoptosis in fetal rat heart. Pregnant rats were treated with cocaine subcutaneously (30 and 60 mg/kg per day) starting at day 15 of gestation and were terminated at day 21. Cocaine produced a dose-dependent increase in apoptotic cell death in the fetal heart by 1.3-fold (30 mg/kg per day) and 2.4-fold (60 mg/kg per day) of the control level (1.99+/-0.15%). Cocaine-induced DNA fragmentation in the fetal heart showed characteristic apoptotic ladder. In accordance, cocaine dose-dependently increased activities of caspase-3, caspase-8, and caspase-9 in the fetal heart by 0.5-, 0.6-, and 0.6-fold, respectively, at 30 mg/kg per day, and by 3.3-, 2.9-, and 2.3-fold, respectively, at 60 mg/kg per day. In contrast, cocaine showed no effect on caspase activities in the maternal heart. Bcl-2 and Bax proteins were detected in fetal rat heart, with 2.2-fold higher expression of Bcl-2 than Bax. Cocaine significantly increased Bax protein levels and decreased Bcl-2 protein levels, leading to a 7.5-fold increase in the Bax-to-Bcl-2 ratio in fetal rat heart. We conclude that cocaine causes apoptosis in fetal rat heart in vivo by upregulating the Bax-to-Bcl-2 ratio and increasing caspase activities, which is likely to play an important role in the adverse effects of cocaine on heart development.
Xiao
Y
Y
Center for Perinatal Biology, Department of Pharmacology, Loma Linda University School of Medicine, California 92350, USA.
Xiao
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D
He
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Zhang
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000096:biosynthesis; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005318:Fetal Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D018765:Dopamine Uptake Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020169:Caspases; D003042:Cocaine