Involvement of calcium-mediated apoptotic signals in H2O2-induced MIN6N8a cell death

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Reactive oxygen species are believed to be the central mediators of beta-cell destruction that leads to type I and 2 diabetes, and calcium has been reported to be an important mediator of beta cell death. In the present study, the authors investigated whether Ca2+ plays a role in hydrogen peroxide (H2O2)-induced MIN6N8a mouse beta cell death. Treatment with low concentration H2O2 (50 mu M) was found to be sufficient to reduce MIN6N8a cell viability by 55%, largely via apoptosis. However, this H2O2-induced cell death was near completely blocked by pretreatment with BAPTA/AM (5 mu M), a chelator of intracellular Ca2+ Moreover, the intracellular calcium store channel blockers, such as, xestospongin c and ryanodine, significant protected cells from 50 mu M H2O2-induced cell death and under extracellular Ca2+-free conditions, 50 mu M H2O2 elicited transient [Ca2+](i) increases. In addition, pharmacologic inhibitors of calpain, calcineurin, and calcium/calmodulin-dependent protein kinase 11 were found to have a protective effect on H2O2-induced death. Moreover, H2O2-induced apoptotic signals, such as c-JUN N-terminal kinase activation, cytochrome c release, caspase 3 activation, and poly (ADP-ribose) polymerase cleavage were all down-regulated by the intracellular Ca2+ chelation. These findings show that [Ca2+](i) elevation, possibly due to release from intracellular calcium stores and the subsequent activation of Ca2+-mediated apoptotic signals, critically mediates low concentration H2O2-induced MIN6N8a cell death. These findings suggest that a breakdown of calcium homeostasis by low level of reactive oxygen species may be involved in beta cell destruction during diabetes development. (c) 2006 Published by Elsevier B.V.
Publisher
ELSEVIER SCIENCE BV
Issue Date
2006-10
Language
English
Article Type
Article
Keywords

PANCREATIC BETA-CELLS; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; PERMEABILITY TRANSITION; PROTEIN-KINASES; CA2+ INFLUX; IN-VITRO; MITOCHONDRIAL; ACTIVATION; EXPRESSION

Citation

EUROPEAN JOURNAL OF PHARMACOLOGY, v.547, pp.1 - 9

ISSN
0014-2999
DOI
10.1016/j.ejphar.2006.06.016
URI
http://hdl.handle.net/10203/93235
Appears in Collection
BS-Journal Papers(저널논문)
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