QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.032011v1 71/5/1319    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Related articles in MolPharm Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, H. Articles by Zhang, L. Search for Related Content PubMed PubMed Citation Articles by Zhang, H. Articles by Zhang, L.

Maternal Cocaine Administration Causes an Epigenetic Modification of Protein Kinase C Gene Expression in Fetal Rat Heart

Center for Perinatal Biology, Department of Physiology and Pharmacology (H.Z., L.Z.), and Department of Biochemistry (A.D., T.A.L., L.C.S.), Loma Linda University School of Medicine, Loma Linda, California; and Research Service, Veteran's Affairs Medical Center, Loma Linda California (T.A.L.)

Protein kinase C (PKC) plays a pivotal role in cardioprotection during cardiac ischemia and reperfusion injury. Recent studies demonstrated that prenatal cocaine exposure caused a decrease in PKC expression and increased heart susceptibility to ischemic injury in adult offspring, suggesting an in utero programming of PKC gene expression pattern in the heart. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for cocaine-mediated repression of the PKC gene in the heart. Pregnant rats were administered either saline or cocaine intraperitoneally (15 mg/kg) twice daily from days 15 to 20 of gestational age, and term fetal hearts were studied. Cocaine treatment significantly decreased PKC mRNA and protein levels in the heart. CpG dinucleotides found in cAMP response element-binding protein (CREB), CREB/c-Jun1, and CREB/c-Jun2 binding sites at the proximal promoter region of the PKC gene were densely methylated and were not affected by cocaine. In contrast, methylation of CpGs in the activator protein 1 (AP-1) binding sites was low but was significantly increased by cocaine. Reporter gene assays showed that the AP-1 binding site played a strong stimulatory role of PKC gene transcription. Methylation of the AP-1 binding sites significantly decreased AP-1 binding to the PKC promoter. Supershift analyses implicated c-Jun homodimers binding to the AP-1 binding sites. Cocaine did not affect nuclear c-Jun levels or the binding of c-Jun to the unmethylated AP-1 binding sites. The results indicate a role for DNA methylation in cocaine-mediated PKC gene repression in the developing heart and suggest an epigenetic mechanism affecting this gene linked with vulnerability of ischemic injury in the heart of adult offspring.

Address correspondence to: Dr. Lubo Zhang, Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350. E-mail: lzhang{at}llu.edu

Related articles in MolPharm:

The Thrill Can Kill: Murder by Methylation

Sailen Barik
MolPharm 2007 71: 1203-1205. [Abstract] [Full Text]  

This article has been cited by other articles:

				H. Zhang, K. D. Meyer, and L. Zhang Fetal Exposure to Cocaine Causes Programming of Prkce Gene Repression in the Left Ventricle of Adult Rat Offspring Biol Reprod, March 1, 2009; 80(3): 440 - 448. [Abstract] [Full Text] [PDF]

				K. D. Meyer and L. Zhang Short- and long-term adverse effects of cocaine abuse during pregnancy on the heart development Therapeutic Advances in Cardiovascular Disease, February 1, 2009; 3(1): 7 - 16. [Abstract] [PDF]

				J. Lawrence, D. Xiao, Q. Xue, M. Rejali, S. Yang, and L. Zhang Prenatal Nicotine Exposure Increases Heart Susceptibility to Ischemia/Reperfusion Injury in Adult Offspring J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 331 - 341. [Abstract] [Full Text] [PDF]