Imperial College London
Alternate

ProfessorJesusGil

Faculty of Medicine, Institute of Clinical Sciences

Professor of Cell Proliferation
 
 
 
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Contact

 

+44 (0)20 3313 8263jesus.gil

 
 
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Location

 

ICTEM room 230ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Born:2023:10.1161/CIRCULATIONAHA.122.058794,
author = {Born, E and Lipskaia, L and Breau, M and Houssaini, A and Beaulieu, DP and Marcos, E and Pierre, R and Do, Cruzeiro M and Lefevre, M and Derumeaux, G and Bulavin, DV and Delcroix, M and Quarck, R and Reen, V and Gil, J and Bernard, D and Flaman, J-M and Adnot, S and Abid, S},
doi = {10.1161/CIRCULATIONAHA.122.058794},
journal = {Circulation},
pages = {650--666},
title = {Eliminating senescent cells can promote pulmonary hypertension development and progression},
url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.122.058794},
volume = {147},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BACKGROUND: Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models. METHODS: We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16LUC/+) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT+), and rats given monocrotaline. RESULTS: Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI, compared with releva
AU  - Born,E
AU  - Lipskaia,L
AU  - Breau,M
AU  - Houssaini,A
AU  - Beaulieu,DP
AU  - Marcos,E
AU  - Pierre,R
AU  - Do,Cruzeiro M
AU  - Lefevre,M
AU  - Derumeaux,G
AU  - Bulavin,DV
AU  - Delcroix,M
AU  - Quarck,R
AU  - Reen,V
AU  - Gil,J
AU  - Bernard,D
AU  - Flaman,J-M
AU  - Adnot,S
AU  - Abid,S
DO  - 10.1161/CIRCULATIONAHA.122.058794
EP  - 666
PY  - 2023///
SN  - 0009-7322
SP  - 650
TI  - Eliminating senescent cells can promote pulmonary hypertension development and progression
T2  - Circulation
UR  - http://dx.doi.org/10.1161/CIRCULATIONAHA.122.058794
UR  - https://www.ncbi.nlm.nih.gov/pubmed/36515093
UR  - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.058794
UR  - http://hdl.handle.net/10044/1/101876
VL  - 147
ER  -
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