Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Cell Death & Disease (Impact Factor: 5.01). 06/2012; 3(6):e322. DOI: 10.1038/cddis.2012.66
Source: PubMed


The success of pancreatic β-cells transplantation to treat type 1 diabetes has been hindered by massive β-cell dysfunction and loss of β-cells that follows the procedure. Hypoxia-mediated cell death has been considered one of the main difficulties that must be overcome for transplantation to be regarded as a reliable therapy. Here we have investigated the mechanisms underlying β-cell death in response to hypoxia (1% O(2)). Our studies show that mouse insulinoma cell line 6 (Min6) cells undergo apoptosis with caspase-3 activation occurring as early as 2 h following exposure to hypoxia. Hypoxia induces endoplasmic reticulum stress in Min6 cells leading to activation of the three branches of the unfolded protein response pathway. In response to hypoxia the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) is upregulated. The important role of CHOP in the apoptotic process was highlighted by the rescue of Min6 cells from hypoxia-mediated apoptosis observed in CHOP-knockdown cells. Culturing isolated pancreatic mouse islets at normoxia showed intracellular hypoxia with accumulation of hypoxia-inducible factor-1α and upregulation of CHOP, the latter one occurring as early as 4 h after isolation. Finally, we observed that pancreatic islets of type 2 db/db diabetic mice were more hypoxic than their counterpart in normoglycemic animals. This finding indicates that hypoxia-mediated apoptosis may occur in type 2 diabetes.

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    • "In vivo study has shown that IH treatment for 2 weeks have increased β-cell apoptosis due to oxidative stress.23 In Min6 cells, an increased activation of caspase-3 was detected after hypoxia treatment, suggesting that Min6 cell apoptosis occurs after a short period of hypoxia exposure.24 However, work from Ota et al.25 has detected that 24 h of IH treatment (1% O2) stimulates β-cells to induce IL-6 gene expression accompanied by a high expression of Reg family genes as well as HGF gene, consequently stimulating β-cell proliferation and inhibiting β-cell apoptosis. "
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    • "NO has been described as a potent inducer of mitochondrial apoptosis [62], especially for cardiomyocytes [63], pancreatic cells [64] and chondrocytes [65]. The use of hypoxic conditions was also reported to activate the apoptotic program in pancreatic cells [66] or cardiomyocytes [67]. The advantages of the lethal-environmental-conditioning strategy rely on the minimal cost and simplicity of the setup required to modulate and control the operating conditions. "

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    • "Decreasing translation by knock-down of aminoacyl tRNA synthase genes reduces expression of UPR mediators, and increases survival in anoxia (Anderson et al., 2009). UPR activity is increased by decreased O 2 in pancreatic β-cells and liver (but not cardiomyocytes), suggesting that it plays a conserved role in the cellular response to hypoxia (Tagliavacca et al., 2012; Zheng et al., 2012). Understanding general mechanisms that integrate stress homeostasis pathways with the proteostasis network could reveal new strategies to manipulate proteostasis. "
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