Bhagwani, A.R., Ali, M., Piper, B. et al. (16 more authors) (2023) A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3. iScience, 26 (2). 105935. ISSN 2589-0042
Abstract
Pulmonary arterial hypertension (PAH) features pathogenic and abnormal endothelial cells (ECs), and one potential origin is clonal selection. We studied the role of p53 and toll-like receptor 3 (TLR3) in clonal expansion and pulmonary hypertension (PH) via regulation of bone morphogenetic protein (BMPR2) signaling. ECs of PAH patients had reduced p53 expression. EC-specific p53 knockout exaggerated PH, and clonal expansion reduced p53 and TLR3 expression in rat lung CD117+ ECs. Reduced p53 degradation (Nutlin 3a) abolished clonal EC expansion, induced TLR3 and BMPR2, and ameliorated PH. Polyinosinic/polycytidylic acid [Poly(I:C)] increased BMPR2 signaling in ECs via enhanced binding of interferon regulatory factor-3 (IRF3) to the BMPR2 promoter and reduced PH in p53−/− mice but not in mice with impaired TLR3 downstream signaling. Our data show that a p53/TLR3/IRF3 axis regulates BMPR2 expression and signaling in ECs. This link can be exploited for therapy of PH.
Metadata
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Copyright, Publisher and Additional Information: | © 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). | ||||
Keywords: | Rare Diseases; Lung; Cardiovascular | ||||
Dates: |
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease | ||||
Funding Information: |
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 16 Jan 2023 12:23 | ||||
Last Modified: | 16 Jan 2023 12:23 | ||||
Published Version: | http://dx.doi.org/10.1016/j.isci.2023.105935 | ||||
Status: | Published | ||||
Publisher: | Elsevier BV | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1016/j.isci.2023.105935 |