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lüll Modulation of apoptosis pathways by oxidative stress and autophagy in beta cells Wang M; Crager M; Pugazhenthi SExp Diabetes Res 2012[]; 2012 (ä): 647914Human islets isolated for transplantation are exposed to multiple stresses including oxidative stress and hypoxia resulting in significant loss of functional beta cell mass. In this study we examined the modulation of apoptosis pathway genes in islets exposed to hydrogen peroxide, peroxynitrite, hypoxia, and cytokines. We observed parallel induction of pro- and antiapoptotic pathways and identified several novel genes including BFAR, CARD8, BNIP3, and CIDE-A. As BNIP3 is an inducer of autophagy, we examined this pathway in MIN6 cells, a mouse beta cell line and in human islets. Culture of MIN6 cells under low serum conditions increased the levels of several proteins in autophagy pathway, including ATG4, Beclin 1, LAMP-2, and UVRAG. Amino acid deprivation led to induction of autophagy in human islets. Preconditioning of islets with inducers of autophagy protected them from hypoxia-induced apoptosis. However, induction of autophagy during hypoxia exacerbated apoptotic cell death. ER stress led to induction of autophagy and apoptosis in beta cells. Overexpression of MnSOD, an enzyme that scavenges free radicals, resulted in protection of MIN6 cells from cytokine-induced apoptosis. Ceramide, a mediator of cytokine-induced injury, reduced the active phosphorylated form of Akt and downregulated the promoter activity of the antiapoptotic gene bcl-2. Furthermore, cytokine-stimulated JNK pathway downregulated the bcl-2 promoter activity which was reversed by preincubation with SP600125, a JNK inhibitor. Our findings suggest that beta cell apoptosis by multiple stresses in islets isolated for transplantation is the result of orchestrated gene expression in apoptosis pathway.|Animals[MESH]|Apoptosis/*drug effects/genetics[MESH]|Autophagy/*drug effects/genetics[MESH]|Cell Line[MESH]|Cells, Cultured[MESH]|Cytokines/pharmacology[MESH]|Gene Expression Profiling[MESH]|Humans[MESH]|Hydrogen Peroxide/pharmacology[MESH]|Insulin-Secreting Cells/drug effects/*metabolism[MESH]|Mice[MESH]|Oxidative Stress/*drug effects/genetics[MESH]|Peroxynitrous Acid/pharmacology[MESH] |