Cocaine and Apoptosis in the Developing Heart

Summary

Principal Investigator: Lubo Zhang
Abstract: 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.
Funding Period: 2001-07-15 - 2006-05-31
more information: NIH RePORT

Top Publications

  1. pmc Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease
    Fuxia Xiong
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, United States
    Front Neuroendocrinol 34:27-46. 2013
  2. pmc Fetal stress and programming of hypoxic/ischemic-sensitive phenotype in the neonatal brain: mechanisms and possible interventions
    Yong Li
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Prog Neurobiol 98:145-65. 2012
  3. pmc Hypoxia and fetal heart development
    A J Patterson
    Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Curr Mol Med 10:653-66. 2010
  4. pmc Short- and long-term adverse effects of cocaine abuse during pregnancy on the heart development
    Kurt D Meyer
    Center for Perinatal Biology, Department of Physiology Pharmacology and Biochemistry, Loma Linda University, School of Medicine, Loma Linda, California 92350, USA
    Ther Adv Cardiovasc Dis 3:7-16. 2009
  5. ncbi Fetal programming of cardiac function and disease
    Kurt Meyer
    Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, California 92350, USA
    Reprod Sci 14:209-16. 2007
  6. pmc Maternal cocaine administration causes an epigenetic modification of protein kinase Cepsilon gene expression in fetal rat heart
    Haitao Zhang
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Mol Pharmacol 71:1319-28. 2007
  7. ncbi Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart
    Sonnet S Jonker
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, USA
    J Appl Physiol (1985) 102:1130-42. 2007
  8. ncbi Fetal and neonatal nicotine exposure differentially regulates vascular contractility in adult male and female offspring
    Daliao Xiao
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    J Pharmacol Exp Ther 320:654-61. 2007
  9. ncbi Regulation of alpha1-adrenoceptor-mediated contractions of uterine arteries by PKC: effect of pregnancy
    Hongying Zhang
    Center for Perinatal Biology, Dept of Physiology and Pharmacology, Loma Linda Univ School of Medicine, Loma Linda, CA 92350, USA
    Am J Physiol Heart Circ Physiol 291:H2282-9. 2006
  10. ncbi Regulation of baseline Ca2+ sensitivity in permeabilized uterine arteries: effect of pregnancy
    Daliao Xiao
    Department of Physiology and Pharmacology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Am J Physiol Heart Circ Physiol 291:H413-20. 2006

Scientific Experts

Detail Information

Publications19

  1. pmc Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease
    Fuxia Xiong
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, United States
    Front Neuroendocrinol 34:27-46. 2013
    ....
  2. pmc Fetal stress and programming of hypoxic/ischemic-sensitive phenotype in the neonatal brain: mechanisms and possible interventions
    Yong Li
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Prog Neurobiol 98:145-65. 2012
    ....
  3. pmc Hypoxia and fetal heart development
    A J Patterson
    Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Curr Mol Med 10:653-66. 2010
    ..The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation...
  4. pmc Short- and long-term adverse effects of cocaine abuse during pregnancy on the heart development
    Kurt D Meyer
    Center for Perinatal Biology, Department of Physiology Pharmacology and Biochemistry, Loma Linda University, School of Medicine, Loma Linda, California 92350, USA
    Ther Adv Cardiovasc Dis 3:7-16. 2009
    ....
  5. ncbi Fetal programming of cardiac function and disease
    Kurt Meyer
    Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, California 92350, USA
    Reprod Sci 14:209-16. 2007
    ..This review gives an overview of the changes that have been observed in the heart in response to various programming stimuli and potential programming mechanisms...
  6. pmc Maternal cocaine administration causes an epigenetic modification of protein kinase Cepsilon gene expression in fetal rat heart
    Haitao Zhang
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Mol Pharmacol 71:1319-28. 2007
    ....
  7. ncbi Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart
    Sonnet S Jonker
    Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, USA
    J Appl Physiol (1985) 102:1130-42. 2007
    ..These data on normal cardiac growth may enable a more detailed understanding of the consequences of experimental and pathological interventions in prenatal life...
  8. ncbi Fetal and neonatal nicotine exposure differentially regulates vascular contractility in adult male and female offspring
    Daliao Xiao
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    J Pharmacol Exp Ther 320:654-61. 2007
    ..The results suggest that fetal and neonatal nicotine exposure alters vascular functions in adult offspring in a gender-specific manner, which may lead to an increased risk of cardiovascular dysfunction in later life...
  9. ncbi Regulation of alpha1-adrenoceptor-mediated contractions of uterine arteries by PKC: effect of pregnancy
    Hongying Zhang
    Center for Perinatal Biology, Dept of Physiology and Pharmacology, Loma Linda Univ School of Medicine, Loma Linda, CA 92350, USA
    Am J Physiol Heart Circ Physiol 291:H2282-9. 2006
    ....
  10. ncbi Regulation of baseline Ca2+ sensitivity in permeabilized uterine arteries: effect of pregnancy
    Daliao Xiao
    Department of Physiology and Pharmacology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Am J Physiol Heart Circ Physiol 291:H413-20. 2006
    ..In addition, PKC plays an important role in the regulation of basal Ca2+ sensitivity, which is downregulated during pregnancy...
  11. ncbi Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway
    Daliao Xiao
    Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Am J Physiol Heart Circ Physiol 290:H2337-43. 2006
    ....
  12. ncbi Gender differences in cardioprotection against ischemia/reperfusion injury in adult rat hearts: focus on Akt and protein kinase C signaling
    Soochan Bae
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    J Pharmacol Exp Ther 315:1125-35. 2005
    ..The results suggest that increased p-Akt and p-PKCepsilon levels in female hearts contribute to the gender-related differences in heart susceptibility to I/R and play an important role in cardioprotection against I/R injury in females...
  13. ncbi Effects of cocaine on nitric oxide production in bovine coronary artery endothelial cells
    Jiale He
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, CA 92350, USA
    J Pharmacol Exp Ther 314:980-6. 2005
    ..Collectively, the results suggest that cocaine inhibits nitric oxide release in BCAECs by decreasing intracellular calcium mobilization, increasing the inactive state of eNOS, and decreasing eNOS protein levels...
  14. pmc Prenatal cocaine exposure increases apoptosis of neonatal rat heart and heart susceptibility to ischemia-reperfusion injury in 1-month-old rat
    Soochan Bae
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Br J Pharmacol 144:900-7. 2005
    ..The results suggest that prenatal cocaine exposure induces abnormal apoptosis and myocyte hypertrophy in postnatal heart, leading to an increased heart susceptibility to ischemic insults in postnatal life...
  15. pmc Prenatal cocaine exposure increases heart susceptibility to ischaemia-reperfusion injury in adult male but not female rats
    Soochan Bae
    Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    J Physiol 565:149-58. 2005
    ..These results suggest that prenatal cocaine exposure causes a sex-specific increase in heart susceptibility to I/R injury in adult male offspring, and the decreased PKCepsilon gene expression in the male heart may play an important role...
  16. ncbi Alpha1-adrenoceptor-mediated phosphorylation of MYPT-1 and CPI-17 in the uterine artery: role of ERK/PKC
    Daliao Xiao
    Center for Perinatal Biology, Dept of Pharmacology and Physiology, Loma Linda Univ School of Medicine, Loma Linda, CA 92350, USA
    Am J Physiol Heart Circ Physiol 288:H2828-35. 2005
    ..In addition, phosphorylated CPI-17 may regulate Ca(2+) sensitivity by interacting with caldesmon and reversing its inhibitory effect on myosin ATPase...
  17. ncbi Prenatal hypoxia and cardiac programming
    Lubo Zhang
    Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California 92350, USA
    J Soc Gynecol Investig 12:2-13. 2005
    ..This review discusses recent evidence of an association of prenatal hypoxic exposure with an increased vulnerability of adult heart disease, and the possible mechanisms involved...
  18. ncbi Cocaine induces apoptosis in fetal rat myocardial cells through the p38 mitogen-activated protein kinase and mitochondrial/cytochrome c pathways
    Guohu Li
    Center for Perinatal Biology, Department of Pharmacology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    J Pharmacol Exp Ther 312:112-9. 2005
    ..In contrast, p38beta MAPK and ERK protect fetal myocardial cells against apoptosis...
  19. ncbi Adaptation of uterine artery thick- and thin-filament regulatory pathways to pregnancy
    Daliao Xiao
    Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
    Am J Physiol Heart Circ Physiol 288:H142-8. 2005
    ..In contrast, pregnancy downregulates the Ca(2+) sensitivity of myofilaments, which is mediated by both thick- and thin-filament pathways...