Imperial College London
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ProfessorAnnaRandi

Faculty of Medicine, National Heart & Lung Institute

Head of Section for Vascular Science
 
 
 
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Contact

 

a.randi Website

 
 
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Location

 

L-block, room 533Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Schafer:2023:10.1101/2023.02.08.527788,
author = {Schafer, CM and Martin-Almedina, S and Kurylowicz, K and Dufton, N and Osuna-Almagro, L and Wu, M-L and Johnson, CF and Shah, AV and Haskard, DO and Buxton, A and Willis, E and Wheeler, K and Turner, S and Chlebicz, M and Scott, RP and Kovats, S and Cleuren, A and Birdsey, GM and Randi, AM and Griffin, CT},
doi = {10.1101/2023.02.08.527788},
journal = {bioRxiv},
title = {Cytokine-Mediated Degradation of the Transcription Factor ERG Impacts the Pulmonary Vascular Response to Systemic Inflammatory Challenge.},
url = {http://dx.doi.org/10.1101/2023.02.08.527788},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BACKGROUND: During infectious diseases, pro-inflammatory cytokines transiently destabilize interactions between adjacent vascular endothelial cells (ECs) to facilitate the passage of immune molecules and cells into tissues. However, in the lung the resulting vascular hyperpermeability can lead to organ dysfunction. Previous work identified the transcription factor ERG as a master regulator of endothelial homeostasis. Here we investigate whether the sensitivity of pulmonary blood vessels to cytokine-induced destabilization is due to organotypic mechanisms affecting the ability of endothelial ERG to protect lung ECs from inflammatory injury. METHODS: Cytokine-dependent ubiquitination and proteasomal degradation of ERG was analyzed in cultured Human Umbilical Vein ECs (HUVECs). Systemic administration of TNFα or the bacterial cell wall component lipopolysaccharide (LPS) was used to cause a widespread inflammatory challenge in mice; ERG protein levels were assessed by immunoprecipitation, immunoblot, and immunofluorescence. Murine Erg deletion was genetically induced in ECs ( Erg fl/fl ;Cdh5(PAC)Cre ERT2 ), and multiple organs were analyzed by histology, immunostaining, and electron microscopy. RESULTS: In vitro, TNFα promoted the ubiquitination and degradation of ERG in HUVECs, which was blocked by the proteasomal inhibitor MG132. In vivo, systemic administration of TNFα or LPS resulted in a rapid and substantial degradation of ERG within lung ECs, but not ECs of the retina, heart, liver, or kidney. Pulmonary ERG was also downregulated in a murine model of influenza infection. Erg fl/fl ;Cdh5(PAC)-Cre ERT2 mice spontaneously recapitulated aspects of inflammatory challenges, including lung-predominant vascular hyperpermeability, immune cell recruitment, and fibrosis. These phenotypes were associated with a lung-specific decrease in the expression of Tek , a gene target of ERG previously implicated in maintaining pulmonary vascular stability during infl
AU  - Schafer,CM
AU  - Martin-Almedina,S
AU  - Kurylowicz,K
AU  - Dufton,N
AU  - Osuna-Almagro,L
AU  - Wu,M-L
AU  - Johnson,CF
AU  - Shah,AV
AU  - Haskard,DO
AU  - Buxton,A
AU  - Willis,E
AU  - Wheeler,K
AU  - Turner,S
AU  - Chlebicz,M
AU  - Scott,RP
AU  - Kovats,S
AU  - Cleuren,A
AU  - Birdsey,GM
AU  - Randi,AM
AU  - Griffin,CT
DO  - 10.1101/2023.02.08.527788
PY  - 2023///
TI  - Cytokine-Mediated Degradation of the Transcription Factor ERG Impacts the Pulmonary Vascular Response to Systemic Inflammatory Challenge.
T2  - bioRxiv
UR  - http://dx.doi.org/10.1101/2023.02.08.527788
UR  - https://www.ncbi.nlm.nih.gov/pubmed/36798267
ER  -
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