Modulation of apoptosis pathways by oxidative stress and autophagy in β cells.

Experimental Diabetes Research Pub Date : 2012-01-01 Epub Date: 2012-03-12 DOI:10.1155/2012/647914
Maorong Wang, Mia Crager, Subbiah Pugazhenthi
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引用次数: 38

Abstract

Human islets isolated for transplantation are exposed to multiple stresses including oxidative stress and hypoxia resulting in significant loss of functional β 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 β 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 β cell apoptosis by multiple stresses in islets isolated for transplantation is the result of orchestrated gene expression in apoptosis pathway.

Abstract Image

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氧化应激和自噬对β细胞凋亡途径的调节。
分离用于移植的人类胰岛暴露于多种应激,包括氧化应激和缺氧,导致功能性β细胞团的显著损失。在这项研究中,我们研究了暴露于过氧化氢、过氧亚硝酸盐、缺氧和细胞因子的胰岛细胞凋亡途径基因的调节。我们观察到平行诱导的促凋亡和抗凋亡途径,并鉴定了几个新基因,包括BFAR, CARD8, BNIP3和CIDE-A。由于BNIP3是一种自噬诱导剂,我们在小鼠β细胞系MIN6细胞和人胰岛中检测了这一途径。低血清条件下培养MIN6细胞后,自噬途径中ATG4、Beclin 1、LAMP-2、UVRAG等蛋白水平升高。氨基酸剥夺导致胰岛细胞自噬的诱导。用自噬诱导剂预处理胰岛可保护其免受缺氧诱导的细胞凋亡。然而,缺氧诱导的自噬加剧了凋亡细胞的死亡。内质网应激诱导β细胞自噬和凋亡。MnSOD是一种清除自由基的酶,其过表达可保护MIN6细胞免受细胞因子诱导的凋亡。神经酰胺是细胞因子诱导损伤的介质,可降低Akt的活性磷酸化形式,下调抗凋亡基因bcl-2的启动子活性。此外,细胞因子刺激的JNK通路下调了bcl-2启动子活性,而用JNK抑制剂SP600125预孵育可以逆转这一活性。我们的研究结果表明,移植胰岛中β细胞在多种应激下的凋亡是凋亡通路中基因表达的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Experimental Diabetes Research
Experimental Diabetes Research 医学-内分泌学与代谢
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审稿时长
3-8 weeks
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