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A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3. iScience 2023 Feb 17;26(2):105935

Date

01/24/2023

Pubmed ID

36685041

Pubmed Central ID

PMC9852960

DOI

10.1016/j.isci.2023.105935

Scopus ID

2-s2.0-85146292305 (requires institutional sign-in at Scopus site)   8 Citations

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.

Author List

Bhagwani AR, Ali M, Piper B, Liu M, Hudson J, Kelly N, Bogamuwa S, Yang H, Londino JD, Bednash JS, Farkas D, Mallampalli RK, Nicolls MR, Ryan JJ, Thompson AAR, Chan SY, Gomez D, Goncharova EA, Farkas L

Author

Hu Yang PhD Chair, Professor in the Biomedical Engineering department at Medical College of Wisconsin