Nitric oxide induces apoptosis in megakaryocytic cell lines.
Cytokines that stimulate inducible nitric oxide (NO) synthase can suppress the growth and differentiation of normal human bone marrow cells, including megakaryocytes. Since NO promotes apoptosis in other cell systems, we chose to study the determinants of apoptosis in megakaryocytic cells. We show that both exogenous and endogenous sources of NO can induce apoptosis in megakaryocytoid cell lines. The megakaryocyte growth factor thrombopoietin suppresses NO-induced apoptosis, whereas treatment with peroxynitrite, a cytotoxic product formed when NO reacts with superoxide, promotes apoptosis. Superoxide inhibitors suppress NO-induced apoptosis, and pretreatment with megakaryocyte growth and maturation factors attenuates NO-induced apoptosis. These data show that NO modulates megakaryocyte apoptosis and suggest that this process may occur in the cytokine-rich marrow milieu to regulate megakaryocyte turnover.
Battinelli
E
E
Whitaker Cardiovascular Institute, Boston, MA, USA.
Loscalzo
J
J
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D002460:Cell Line; D018920:Coculture Techniques; D004249:DNA Damage; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D007213:Indomethacin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology; D010117:Oxypurinol / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D026422:S-Nitrosoglutathione; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides; D013926:Thrombopoietin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D000975:Antioxidants; D009603:Nitroso Compounds; D010975:Platelet Aggregation Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D013926:Thrombopoietin; D002374:Catalase; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D010117:Oxypurinol; D005978:Glutathione; D007213:Indomethacin