Adenoviral TMBIM6 vector attenuates ER-stress-induced apoptosis in a neonatal hypoxic-ischemic rat model

Desislava Doycheva, Ningbo Xu, Harpreet Kaur, Jay Malaguit, Devin William McBride, Jiping Tang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Endoplasmic reticulum (ER) stress is a major pathology encountered after hypoxic-ischemic (HI) injury. Accumulation of unfolded proteins triggers the unfolded protein response (UPR), resulting in the activation of pro-apoptotic cascades that lead to cell death. Here, we identified Bax inhibitor 1 (BI-1), an evolutionarily conserved protein encoded by the transmembrane BAX inhibitor motif-containing 6 ( TMBIM6) gene, as a novel modulator of ER-stress-induced apoptosis after HI brain injury in a neonatal rat pup. The main objective of our study was to overexpress BI-1, via viral-mediated gene delivery of human adenoviral-TMBIM6 (Ad-TMBIM6) vector, to investigate its anti-apoptotic effects as well as to elucidate its signaling pathways in an in vivo neonatal HI rat model and in vitro oxygen-glucose deprivation (OGD) model. Ten-day-old unsexed Sprague Dawley rat pups underwent right common carotid artery ligation followed by 1.5 h of hypoxia. Rat pups injected with Ad-TMBIM6 vector, 48 h pre-HI, showed a reduction in relative infarcted area size, attenuated neuronal degeneration and improved long-term neurological outcomes. Furthermore, silencing of BI-1 or further activating the IRE1α branch of the UPR, using a CRISPR activation plasmid, was shown to reverse the protective effects of BI-1. Based on our in vivo and in vitro data, the protective effects of BI-1 are mediated via inhibition of IRE1α signaling and in part via inhibition of the second stress sensor receptor, PERK. Overall, this study showed a novel role for BI-1 and ER stress in the pathophysiology of HI and could provide a basis for BI-1 as a potential therapeutic target.

Original languageEnglish
Article numberdmm.040352
JournalDMM Disease Models and Mechanisms
Volume12
Issue number11
DOIs
StatePublished - Nov 2019

ASJC Scopus Subject Areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology

Keywords

  • Apoptosis
  • Bax inhibitor 1
  • ER stress
  • Neonatal hypoxia ischemia
  • TMBIM6
  • Animals, Newborn
  • Endoribonucleases/physiology
  • Transcription Factor CHOP/physiology
  • X-Box Binding Protein 1/physiology
  • Signal Transduction
  • Endoplasmic Reticulum Stress/physiology
  • Membrane Proteins/genetics
  • Rats
  • Unfolded Protein Response
  • Multienzyme Complexes/physiology
  • Rats, Sprague-Dawley
  • Animals
  • Maze Learning
  • Protein Serine-Threonine Kinases/physiology
  • Adenoviridae/genetics
  • Apoptosis Regulatory Proteins/genetics
  • Genetic Vectors
  • Hypoxia-Ischemia, Brain/etiology
  • Disease Models, Animal

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