Nitric oxide induces apoptosis via Ca2+-dependent processes in the pancreatic beta-cell line MIN6.
An excessive production of nitric oxide (NO) in response to cytokines has been shown to be the major cause of the destruction of islet beta-cells associated with type 1 (insulin-dependent) diabetes mellitus. The NO-induced beta-cell death is the typical apoptosis. In the present study, we show evidence that supports a tight link between NO, Ca2+, protease and apoptosis in beta-cells. Three different NO donors, SNAP, NOR3 and NOC7, induced apoptosis in a beta-cell line, MIN6 cells, in a concentration-dependent manner. SNAP at 200 microM increased cytosolic Ca2+ concentration ([Ca2+]i) and induced apoptosis. The SNAP-induced apoptosis was blocked by a Ca2+ chelator, BAPTA-AM, and by an inhibitor of a Ca2+-dependent protease, calpain. In conclusion, an excessive NO production induces apoptosis, wherein an increase in [Ca2+]i and resultant activation of calpain play a key role.
Nakata
M
M
Department of Laboratory Medicine, Faculty of Medicine, Kagoshima University, Japan.
Uto
N
N
Maruyama
I
I
Yada
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000503:physiopathology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007340:Insulinoma / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002614:Chelating Agents; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D009569:Nitric Oxide; D004533:Egtazic Acid; D010396:Penicillamine; D002118:Calcium