PMID- 34226528
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210724
IS  - 2058-7716 (Print)
IS  - 2058-7716 (Electronic)
IS  - 2058-7716 (Linking)
VI  - 7
IP  - 1
DP  - 2021 Jun 29
TI  - Endothelial-specific insulin receptor substrate-1 overexpression worsens neonatal 
      hypoxic-ischemic brain injury via mTOR-mediated tight junction disassembly.
PG  - 150
LID - 10.1038/s41420-021-00548-3 [doi]
LID - 150
AB  - Hypoxic-ischemic (HI) encephalopathy is the major cause of mortality and 
      disability in newborns. The neurovascular unit is a major target of acute and 
      chronic brain injury, and therapies that protect simultaneously both neurons and 
      vascular endothelial cells from neonatal HI injury are in demand. Insulin 
      receptors and its key downstream molecule-insulin receptor substrate -1 (IRS-1) 
      are potential neuroprotective targets and expressed both in neuron and 
      endothelial cells. To investigate whether IRS-1 can act similarly in neurons and 
      vascular endothelial cells in protecting neurovascular units and brain form HI 
      injury, we found that neuron-specific IRS-1 transgenic rats showed reduced 
      neurovascular injury and infarct volumes, whereas endothelial-specific IRS-1 
      transgenic rats showed increased blood-brain barrier (BBB) disruption and 
      exaggerated neurovascular injury after neonatal HI brain injury. 
      Endothelial-specific IRS-1 overexpression increased vascular permeability and 
      disassembled the tight junction protein (zonula occludens-1) complex. Inhibition 
      of mammalian target of rapamycin (mTOR) by rapamycin preserved tight junction 
      proteins and attenuated BBB leakage and neuronal apoptosis after HI in the 
      endothelial-specific IRS-1 transgenic pups. Together, our findings suggested that 
      neuronal and endothelial IRS-1 had opposite effects on the neurovascular 
      integrity and damage after neonatal HI brain injury and that endothelial IRS-1 
      worsens neurovascular integrity after HI via mTOR-mediated tight junction protein 
      disassembly.
FAU - Tu, Yi-Fang
AU  - Tu YF
AUID- ORCID: 0000-0002-9498-6178
AD  - Department of Pediatrics, National Cheng Kung University Hospital, College of 
      Medicine, National Cheng Kung University, Tainan, Taiwan. nckutu@gmail.com.
AD  - Institute of Clinical Medicine, College of Medicine, National Cheng Kung 
      University, Tainan, Taiwan. nckutu@gmail.com.
FAU - Jiang, Si-Tse
AU  - Jiang ST
AD  - National Laboratory Animal Center, National Applied Research Laboratories, 
      Taipei, Taiwan.
FAU - Chiang, Chi-Wu
AU  - Chiang CW
AD  - Institute of Molecular Medicine, College of Medicine, National Cheng Kung 
      University, Tainan, Taiwan.
FAU - Chen, Li-Ching
AU  - Chen LC
AD  - TMU Research Center of Cancer Translational Medicine, Taipei Medical University, 
      Taipei, Taiwan.
FAU - Huang, Chao-Ching
AU  - Huang CC
AD  - Department of Pediatrics, National Cheng Kung University Hospital, College of 
      Medicine, National Cheng Kung University, Tainan, Taiwan.
LA  - eng
GR  - NCKUH-10105002/National Cheng Kung University Hospital (NCKU Hospital)/
PT  - Journal Article
DEP - 20210629
PL  - United States
TA  - Cell Death Discov
JT  - Cell death discovery
JID - 101665035
PMC - PMC8257791
COIS- The authors declare no competing interests.
EDAT- 2021/07/07 06:00
MHDA- 2021/07/07 06:01
PMCR- 2021/06/29
CRDT- 2021/07/06 05:59
PHST- 2021/02/12 00:00 [received]
PHST- 2021/06/09 00:00 [accepted]
PHST- 2021/05/09 00:00 [revised]
PHST- 2021/07/06 05:59 [entrez]
PHST- 2021/07/07 06:00 [pubmed]
PHST- 2021/07/07 06:01 [medline]
PHST- 2021/06/29 00:00 [pmc-release]
AID - 10.1038/s41420-021-00548-3 [pii]
AID - 548 [pii]
AID - 10.1038/s41420-021-00548-3 [doi]
PST - epublish
SO  - Cell Death Discov. 2021 Jun 29;7(1):150. doi: 10.1038/s41420-021-00548-3.