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MiR-17 Downregulation by High Glucose Stabilizes Thioredoxin-Interacting Protein and Removes Thioredoxin Inhibition on ASK1 Leading to Apoptosis.

ABSTRACT: Pregestational diabetes significantly increases the risk of neural tube defects (NTDs). Maternal diabetes activates an Apoptosis Signal-regulating Kinase 1 (ASK1)-initiated pathway, which triggers neural stem cell apoptosis of the developing neuroepithelium leading to NTD formation. How high glucose of diabetes activates ASK1 is still unclear. In this study, we investigated the mechanism underlying high glucose-induced ASK1 activation. High glucose suppressed miR-17 expression, which led to an increase in its target gene Txnip (Thioredoxin-interacting protein). High glucose-increased Txnip enhanced its binding to the ASK1 inhibitor, thioredoxin (Trx), and thereby sequestered Trx from the Trx-ASK1 complex. High glucose-induced ASK1 activation and consequent apoptosis were abrogated by either the miR-17 mimic or Txnip siRNA knockdown. In contrast, the miR-17 inhibitor or Txnip ectopic overexpression mimicked the stimulative effect of high glucose on ASK1 and apoptosis. Thus, our study demonstrated that miR-17 repression mediates the pro-apoptotic effect of high glucose, and revealed a new mechanism underlying ASK1 activation, in which decreased miR-17 removes Trx inhibition on ASK1 through Txnip.

SUBMITTER: Dong D

PROVIDER: S-EPMC4830238 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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MiR-17 Downregulation by High Glucose Stabilizes Thioredoxin-Interacting Protein and Removes Thioredoxin Inhibition on ASK1 Leading to Apoptosis.

Dong Daoyin D Fu Noah N Yang Peixin P

Toxicological sciences : an official journal of the Society of Toxicology 20151210 1

Pregestational diabetes significantly increases the risk of neural tube defects (NTDs). Maternal diabetes activates an Apoptosis Signal-regulating Kinase 1 (ASK1)-initiated pathway, which triggers neural stem cell apoptosis of the developing neuroepithelium leading to NTD formation. How high glucose of diabetes activates ASK1 is still unclear. In this study, we investigated the mechanism underlying high glucose-induced ASK1 activation. High glucose suppressed miR-17 expression, which led to an i ...[more]

PMID: 26660634

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Project description:BackgroundEarly brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms.MethodsA total of 299 male Sprague-Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood-brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI.ResultsWe found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices.ConclusionsThese results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.

Dataset Information

MiR-17 Downregulation by High Glucose Stabilizes Thioredoxin-Interacting Protein and Removes Thioredoxin Inhibition on ASK1 Leading to Apoptosis.

Publications

MiR-17 Downregulation by High Glucose Stabilizes Thioredoxin-Interacting Protein and Removes Thioredoxin Inhibition on ASK1 Leading to Apoptosis.

Similar Datasets

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