Cocaine use during pregnancy has been associated with numerous adverse perinatal outcomes. Among other effects, cocaine clearly predisposes the fetus and neonate to various cardiovascular dysfunctions. Our preliminary studies indicated that prenatal cocaine exposure caused an increase in apoptosis in near-term fetal rat heart and a decrease in cardiac contractility in newborn rats. Compelling evidence indicates that apoptosis plays a key role in heart development and in several cardiovascular diseases. Yet the cellular/molecular mechanisms underlying cocaine-induced apoptosis in the developing heart are unknown. The proposed studies focus on these mechanisms, and will address the general hypothesis that cocaine increases apoptosis in myocardial cells of the developing heart through nitric oxide (NO) and mitogen-activated protein kinases (MAPKs), leading to mitochondrial cytochrome c release and subsequent activation of the caspase cascade. Four of its main corollaries will be addressed by 4 Specific Aims which will test whether cocaine 1) activates constitutive nitric oxide synthase (NOS) and up-regulates inducible NOS (iNOS), resulting in apoptosis, 2) increases the balance of activities of p38 MAPK/JNK versus ERK resulting in apoptosis, 3) affects Bcl-2 family proteins by increasing the balance of proapoptotic/antiapoptotic proteins and inducing the translocation of proapoptotic proteins to mitochondria, and 4) induces mitochondrial cytochrome c release and subsequent activation of the caspase cascade. To achieve these aims, we propose a series of experiments in primary cultures of fetal rat cardiac myocytes. We will measure NO release and expression of eNOS, nNOS, and iNOS; activities of p38 MAPK, JNK, and ERK; protein levels and subcellular distribution of Bcl-2, Bcl-xL, Bax, and Bad; mitochondrial cytochrome c release; and activities of caspase-3, caspase-8, and caspase-9. The results of the proposed studies will provide a comprehensive and novel assessment of the dynamic interactions among nitric oxide, MAPKs, Bcl-2 family proteins, mitochondrial cytochrome c, and the caspase cascade in cocaine-induced myocyte apoptosis, and will improve our understanding of the adverse effects of cocaine on the developing heart. They will also provide exciting new information to fill the important gaps in our understanding of signaling mechanisms in myocyte apoptosis in general. Such an understanding has obvious clinical implications because the increasing information has pointed to an important role of apoptosis in cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067745-02
Application #
6538052
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Pearson, Gail D
Project Start
2001-07-15
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$205,000
Indirect Cost
Name
Loma Linda University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
Xiong, Fuxia; Zhang, Lubo (2013) Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease. Front Neuroendocrinol 34:27-46
Li, Yong; Gonzalez, Pablo; Zhang, Lubo (2012) Fetal stress and programming of hypoxic/ischemic-sensitive phenotype in the neonatal brain: mechanisms and possible interventions. Prog Neurobiol 98:145-65
Patterson, A J; Zhang, L (2010) Hypoxia and fetal heart development. Curr Mol Med 10:653-66
Meyer, Kurt D; Zhang, Lubo (2009) Short- and long-term adverse effects of cocaine abuse during pregnancy on the heart development. Ther Adv Cardiovasc Dis 3:7-16
Meyer, Kurt; Lubo Zhang (2007) Fetal programming of cardiac function and disease. Reprod Sci 14:209-16
Zhang, Haitao; Darwanto, Agus; Linkhart, Thomas A et al. (2007) Maternal cocaine administration causes an epigenetic modification of protein kinase Cepsilon gene expression in fetal rat heart. Mol Pharmacol 71:1319-28
Xiao, DaLiao; Huang, Xiaohui; Lawrence, Jennifer et al. (2007) Fetal and neonatal nicotine exposure differentially regulates vascular contractility in adult male and female offspring. J Pharmacol Exp Ther 320:654-61
Jonker, Sonnet S; Zhang, Lubo; Louey, Samantha et al. (2007) Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. J Appl Physiol 102:1130-42
Zhang, Hongying; Xiao, Daliao; Longo, Lawrence D et al. (2006) Regulation of alpha1-adrenoceptor-mediated contractions of uterine arteries by PKC: effect of pregnancy. Am J Physiol Heart Circ Physiol 291:H2282-9
Xiao, Daliao; Buchholz, John N; Zhang, Lubo (2006) Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway. Am J Physiol Heart Circ Physiol 290:H2337-43

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