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 language | English |
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Article number | dmm.040352 |
Journal | DMM Disease Models and Mechanisms |
Volume | 12 |
Issue number | 11 |
DOIs | |
State | Published - 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