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Research ArticleCARDIOVASCULAR

Cocaine-Mediated Apoptosis in Bovine Coronary Artery Endothelial Cells: Role of Nitric Oxide

Jiale He, Yuhui Xiao and Lubo Zhang
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 180-187;
Jiale He
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Yuhui Xiao
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Lubo Zhang
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Abstract

The present study examined the role of nitric oxide in cocaine-induced apoptosis in bovine coronary artery endothelial cells (BCAECs). Cocaine produced a time-dependent decrease in cell viability and an increase in apoptosis in BCAECs, which were blocked by the nitric oxide donors DETA-NONOate (DETA-NO) andS-nitroso-N-acetyl-penicillamine. In accordance, cocaine decreased nitric oxide production in BCAECs at each time point of the study. Cocaine significantly increased caspase-3 activity that was blocked by the inhibitors of cytochromec release (cyclosporin A), caspase-3 (Ac-DEVD-CHO), and caspase-9 (Z-LEHD-FMK), respectively. In addition, cocaine activated caspase-9, which was blocked by cyclosporin A and Z-LEHD-FMK. Ac-DEVD-CHO only partially blocked cocaine-induced caspase-9 activity. DETA-NO (20 μM) blocked cocaine-mediated activation of both caspase-9 and caspase-3. Cocaine decreased Bcl-2 protein levels, which was partially blocked by Ac-DEVD-CHO and Z-LEHD-FMK, but not by DETA-NO. Furthermore, cocaine induced a translocation of Bax from the cytosol to the mitochondria in BCAECs, and increased Bax levels in mitochondria by 2.2-fold. In accordance, cytosolic Bax levels decreased about 42%. Neither Ac-DEVD-CHO nor DETA-NO affected cocaine-induced translocation of Bax. We conclude that cocaine-induced Bcl-2 protein down-regulation and Bax translocation to the mitochondria are upstream signals of caspase-9 activation that precedes caspase-3. Cocaine-induced attenuation of nitric oxide plays a key role in the activation of the caspase cascade in BCAECs.

Footnotes

  • This work was supported in part by National Institutes of Health Grants HL-54094, HL-57787, and HD31226; Grant-in-Aid 96007560 from the American Heart Association; and by Loma Linda University School of Medicine.

  • Abbreviations:
    NO
    nitric oxide
    l-NAME
    N-nitro-l-arginine methyl ester
    DETA-NO
    DETA-NONOate
    SNAP
    S-nitroso-N-acetyl-penicillamine
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    BCAEC
    bovine coronary artery endothelial cell
    NOx
    nitrate, nitrite, and nitric oxide
    PAGE
    polyacrylamide gel electrophoresis
    PTP
    permeability transition pore
    ANOVA
    analysis of variance
    • Received October 24, 2000.
    • Accepted March 30, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleCARDIOVASCULAR

Cocaine-Mediated Apoptosis in Bovine Coronary Artery Endothelial Cells: Role of Nitric Oxide

Jiale He, Yuhui Xiao and Lubo Zhang
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 180-187;

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Research ArticleCARDIOVASCULAR

Cocaine-Mediated Apoptosis in Bovine Coronary Artery Endothelial Cells: Role of Nitric Oxide

Jiale He, Yuhui Xiao and Lubo Zhang
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 180-187;
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