Intermittent-Hypoxia-Induced Autophagy Activation Through the ER-Stress-Related PERK/eIF2α/ATF4 Pathway is a Protective Response to Pancreatic β-Cell Apoptosis

Song, Shuling; Tan, Jin; Miao, Yuyang; Sun, Zilong; Zhang, Qiang

doi:10.1159/000496047

Cited by 50 publications

(25 citation statements)

References 44 publications

(50 reference statements)

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“…In addition, caspases were activated in the process of apoptosis [19]. Autophagy is also a type of cell death which degrades and recycles long-lived or damaged proteins and cytoplasmic organelles by lysosomes [20]. During autophagy, p62 protein is degraded while LC3-I is converted to LC3-II [21].…”

Section: Discussionmentioning

confidence: 99%

6-Gingerols (6G) reduces hypoxia-induced PC-12 cells apoptosis and autophagy through regulation of miR-103/BNIP3

Kang

Han

Zhang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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2019) 6-Gingerols (6G) reduces hypoxia-induced PC-12 cells apoptosis and autophagy through regulation of miR-103/BNIP3, Artificial ABSTRACT Finding novel therapeutic agent for the treatment of cerebral ischemia is urgently required. These experiments explored the potential roles of 6-Gingerols (6G) in hypoxia-stimulated rat PC-12 cells. Cell viability, apoptosis and its related proteins were studied by the approaches of MTT assay, flow cytometry assay and Western blot analysis, respectively. In addition, whether 6G achieved its functions in hypoxia-induced injury through miR-103 was illustrated. Moreover, the associated signalling pathways were investigated. Obviously, hypoxia treatment blocked cell viability and enhanced apoptosis while this trend was ameliorated by 6G. Then we observed that hypoxia administration up-regulated miR-103 expression and 6G could further increase miR-103 expression in hypoxia-stimulated PC-12 cells. Inhibition of miR-103 attenuated the neuroprotective effects of 6G on hypoxia-treated PC-12 cells. Moreover, Bcl2/adenovirus EIB 19kD-interacting protein 3 (BNIP3) was a target of miR-103 and BNIP3 upregulation also attenuated the neuroprotective impact of 6G on hypoxia-treated PC-12 cells. Hypoxia activated the p38MAPK and JNK pathways were inactivated by 6G. To sum up, 6G protected hypoxiastimulated PC-12 cells through miR-103-mediatated down-regulation of BNIP3 by inhibiting p38 MAPK and JNK pathways. HIGHLIGHTS 1. 6-Gingerols (6G) is a promising agent for cerebral ischemia therapy. 2. The neuroprotective effects of 6G are mediated by miR-103 and BNIP3. 3. Up-regulation of miR-103 exerts neuroprotective effects. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

6-Gingerols (6G) reduces hypoxia-induced PC-12 cells apoptosis and autophagy through regulation of miR-103/BNIP3

Kang

Han

Zhang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…In fact, from our previous study, we did not observe ER stress activation in the hippocampus after 7 days of IH treatment, but was significantly activated after 14 days of IH treatment [8]. Also, it has been reported that PERK-elf2-ATF-4 arm is activated to induce apoptosis in prolonged IH treatment [30]. Caspase-12 has been proposed as a key mediator under the execution phase of ER stressinduced apoptosis, with its activation by means of excessive ER stress and in turn activating pro-caspase-3, leading to apoptosis [31].…”

Section: Discussionmentioning

confidence: 59%

Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation

Shi

Xie

et al. 2020

BMC Pulm Med

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Background: Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues. Chronic intermittent hypoxia (IH) is considered to be the primary player in OSA, but the mechanisms underlying its effect on pulmonary tissues are unknown. Endoplasmic reticulum (ER) stress induced by IH treatment plays an important role in accelerating the process of fibrosis and induction of apoptosis. Methods: Mice were placed in IH chambers for 4 weeks with an oscillating oxygen (O 2 ) concentration between 5 and 21%, cycling every 90s for 8 h daily. Mice were randomly divided into four groups: control group (normal oxygen), tauroursodeoxycholic acid (TUDCA) group (normal oxygen intraperitoneally injected with TUDCA), IH group and IH + TUDCA group. After 4 weeks, the proteins in three branch signaling pathways of ER stress, including protein kinase RNA (PKR)-like/Pancreatic ER kinase (PERK), activating transcription factor 6 (ATF-6) and inositolrequiring enzyme 1 (IRE-1), were evaluated. The cleaved caspase-3, caspase-12 and TUNNEL staining was assessed. Furthermore, the expression of transforming growth factor-β1 (TGF-β1) and thrombospondin-1(TSP-1), two extracellular matrix proteins that play critical role in fibrosis, were examined. Finally, Masson's trichrome staining was performed to detect the expression of collagen. Results: After 4 weeks of IH treatment, the expressions of two ER stress markers, glucose regulated protein-78 (Grp78) and transcription factor C/EBP homologous protein (CHOP) were increased which was prevented by administration of the ER stress attenuator, TUDCA. The expressions of PERK, but not those of ATF-6 and IRE-1, were increased. The effects of IH were accompanied by an increased number of apoptotic cells and increased expressions of cleaved caspase-3 and caspase-12 in pulmonary tissues. In addition, histological examination suggested the presence of fibrosis after chronic IH treatment, indicated by increased expression of collagen, which was associated with the up-regulation of TGF-β1 and TSP-1 that are known to promote fibrosis. Similarly, TUDCA could reduce the extent of fibrotic area and the expression levels of these proteins. (Continued on next page)Conclusions: It reveals the roles of ER stress, especially the PERK pathway, in IH induced apoptosis and fibrosis in pulmonary tissues that might underlie the pulmonary complications observed in OSA.

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“…In this study, we proved that ATF4-mediated autophagy activation plays a crucial role in IL-22 protecting hepatocytes against LPS-induced damage. Previous investigations described that intermittent hypoxia induced autophagy activation is dependent on PERK/eIF2α/ ATF4 signaling pathway, inhibition of autophagy by chloroquine or deficiency of autophagy-related gene 5 (Atg5) and Atg7 promoted pancreatic β-cell apoptosis 36 . In addition, ATF4 depletion promotes hepatocytes apoptosis by inhibiting autophagy 36,37 .…”

Section: Discussionmentioning

confidence: 99%

“…Previous investigations described that intermittent hypoxia induced autophagy activation is dependent on PERK/eIF2α/ ATF4 signaling pathway, inhibition of autophagy by chloroquine or deficiency of autophagy-related gene 5 (Atg5) and Atg7 promoted pancreatic β-cell apoptosis 36 . In addition, ATF4 depletion promotes hepatocytes apoptosis by inhibiting autophagy 36,37 . Collectively, our study suggests that ATF4 is an essential downstream molecule of IL-22-activated autophagy in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling

et al. 2020

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Uncontrollable inflammatory response acts as a driver of sepsis-associated liver injury (SALI). IL-22 plays an important role in regulating inflammatory responses, but its role in SALI remains unknown. The aim of the study was to assess the association of serum IL-22 with SALI in pediatric patients and to enclose the underlying mechanisms of IL-22 involved in lipopolysaccharide (LPS) - induced acute liver injury (ALI) in mice. Serum IL-22 levels in patients with SALI were significantly lower than in septic patients without liver injury, and the area under receiver operating characteristic (ROC) curve of IL-22 for discriminating SALI was 0.765 (95% CI: 0.593–0.937). Pre-administration of recombinant murine IL-22 alleviated LPS-induced ALI in mice, and serum IL-6 levels and the mRNA levels of TNF-α, IL-1β, and IL-6 in livers were decreased in response to IL-22 pre-treatment in mice. More importantly, IL-22 pre-treatment activated hepatic autophagy mediated by activating transcription factor 4 (ATF4)-autophagy-related gene 7 (ATG7) signaling in vivo and in vitro in response to LPS administration. Moreover, knockdown of ATF4 in mice aggravated LPS-induced ALI, which was associated with suppressed ATG7-related autophagy. In addition, the protective effects of IL-22 on LPS-induced ALI was partially blocked by ATF4 knockdown, which was associated with lower expression of LC3II/I in the livers of ATF4 knockdown (HT or Atf4+/−) mice compared with wild-type mice (WT or Atf4+/+) mice. In conclusion, low serum IL-22 level is associated with SALI occurrence, and IL-22 pre-administration activates autophagy in hepatocytes and protects mice against LPS-induced ALI partially related to ATF4-ATG7 signaling pathway.

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Intermittent-Hypoxia-Induced Autophagy Activation Through the ER-Stress-Related PERK/eIF2α/ATF4 Pathway is a Protective Response to Pancreatic β-Cell Apoptosis

Cited by 50 publications

References 44 publications

6-Gingerols (6G) reduces hypoxia-induced PC-12 cells apoptosis and autophagy through regulation of miR-103/BNIP3

6-Gingerols (6G) reduces hypoxia-induced PC-12 cells apoptosis and autophagy through regulation of miR-103/BNIP3

Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation

IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling

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