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. "
    Y Fang · Q Zhang · J Tan · L Li · X An · P Lei
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    ABSTRACT: Purpose: Obstructive sleep apnea hypopnea syndrome (OSAHS), a common sleep and breathing disorder, is independently associated with metabolic dysfunction, including impaired glucose tolerance and insulin resistance. Intermittent hypoxia (IH), a pathological component of OSAHS, increases oxidative stress damage to pancreatic β-cells in animal models resembling patients with OSAHS. However, the precise mechanisms of IH-induced pancreatic β-cell dysfunction are not fully understood. In the present study, we established a mice model to investigate the underlying mechanisms of oxidative stress in IH-induced pancreatic β-cell apoptosis through antioxidant N-acetylcysteine (NAC) pretreatment. Methods: Twenty-four Wistar rats were randomly divided into four experimental groups: normal control group, intermittent normoxia group, IH group and antioxidant intervention group. Pancreatic β-cell apoptosis rates were detected by terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling; Bcl-2 and Bax protein expressions were detected by immunohistochemistry staining and western blotting. Results: In our study, we demonstrated that IH exposure causes an increased activation of pancreatic β-cell apoptosis compared with that in the normal control group and intermittent normoxia group, accompanied by the downregulation of Bcl-2 and upregulation of Bax (P<0.05). Furthermore, compared with the IH group, antioxidant (NAC) pretreatment significantly decreased IH-mediated β-cell apoptosis and reversed the ratio of Bcl-2/Bax expression (P<0.05). Conclusion: Taken together, these results demonstrate a critical role of oxidative stress in the regulation of apoptosis through Bcl-2 and Bax signaling. The antioxidant NAC has a protective effect against IH-induced pancreatic β-cell apoptosis.
    Nutrition & Diabetes 09/2014; 4(9):e131. DOI:10.1038/nutd.2014.28 · 2.65 Impact Factor
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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. "
    Biomaterials 04/2013; · 8.56 Impact Factor
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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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    ABSTRACT: The ability to sense and respond to stressful conditions is essential to maintain organismal homeostasis. It has long been recognized that stress response factors that improve survival in changing conditions can also influence longevity. In this review, we discuss different strategies used by animals in response to decreased O(2) (hypoxia) to maintain O(2) homeostasis, and consider interactions between hypoxia responses, nutritional status, and H(2)S signaling. O(2) is an essential environmental nutrient for almost all metazoans as it plays a fundamental role in development and cellular metabolism. However, the physiological response(s) to hypoxia depend greatly on the amount of O(2) available. Animals must sense declining O(2) availability to coordinate fundamental metabolic and signaling pathways. It is not surprising that factors involved in the response to hypoxia are also involved in responding to other key environmental signals, particularly food availability. Recent studies in mammals have also shown that the small gaseous signaling molecule hydrogen sulfide (H(2)S) protects against cellular damage and death in hypoxia. These results suggest that H(2)S signaling also integrates with hypoxia response(s). Many of the signaling pathways that mediate the effects of hypoxia, food deprivation, and H(2)S signaling have also been implicated in the control of lifespan. Understanding how these pathways are coordinated therefore has the potential to reveal new cellular and organismal homeostatic mechanisms that contribute to longevity assurance in animals.
    Frontiers in Genetics 11/2012; 3:257. DOI:10.3389/fgene.2012.00257
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