Cyclic-AMP Inhibits Nitric Oxide-Induced Apoptosis in Human Osteoblast: The Regulation of Caspase-3, -6, -9 and the Release of Cytochrome c in Nitric Oxide-Induced Apoptosis by cAMP.

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  • CHAE Han-Jung
    Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University
  • CHAE Soo-Wan
    Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University
  • AN Nyeon-Hyoung
    College of Pharmacy, and School of Oriental Medicine, Wonkwang University
  • KIM Jong-Hwan
    Department of Gynecology, and School of Oriental Medicine, Wonkwang University
  • KIM Chul-Won
    Department of Gynecology, and School of Oriental Medicine, Wonkwang University
  • YOO Sim-Keun
    Department of Gynecology, and School of Oriental Medicine, Wonkwang University
  • KIM Hong-Hee
    National Research Laboratory for Bone Metabolism and Research Center for Proteinous Materials, Chosun University
  • LEE Zang-Hee
    National Research Laboratory for Bone Metabolism and Research Center for Proteinous Materials, Chosun University
  • KIM Hyung-Ryong
    Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University

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Nitric oxide (NO) induces apoptotic cell death and cAMP has a significantly protective effect on NO-induced cytotoxicity in human osteoblasts, MG-63 cells. Treatment with S-nitroso-N-acetylpenicillamine (SNAP)(0.6 mM) resulted in genomic DNA fragmentation, characteristic of apoptosis. However, concomitant incubation of the cells with either DBcAMP or forskolin markedly inhibited SNAP-induced apoptosis in a dose-dependent manner. Furthermore, pretreatment of MG-63 cells with H-89 or KT5720, which is known to inhibit cAMP-dependent protein kinase (PKA), abolished the protective effect of DBcAMP and forskolin on SNAP-induced apoptosis. In this study, we explored the involvement of caspases in the regulatory mechanism of SNAP-induced apoptosis by cAMP. Our data show that DBcAMP or forskolin blocked SNAP-induced caspase-3-like cysteine protease activation and that H-89, a PKA inhibitor, reversed the cAMP-induced regulatory effect of caspase-3 like protease. Consistent with the results, cAMP inhibited the proteolytic cleavage of caspase-3, -6, -9 and cytochrome c release to cytoplasm. The inhibition of caspase-3 activation did not block SNAP-induced cytochrome c release to cytoplasm, suggesting that caspase-3 activation may occur downstream of cytochrome c release. In summary, these findings show that the exposure of MG-63 cells to cAMP analogs renders them more resistant to NO-induced damage and suggests the presence of regulatory mechanisms of the cell death pathway by cAMP in which caspase-3, -6, and -9 and cytochrome c release serves to mediate NO-induced apoptosis.

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