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.
A. R. Bhagwani and M. Ali and B. Piper and M. Liu and J. Hudson and N. Kelly and S. Bogamuwa and H. Yang and J. D. Londino and J. S. Bednash and D. Farkas and R. K. Mallampalli and M. R. Nicolls and J. J. Ryan, "A P53-TLR3 Axis Ameliorates Pulmonary Hypertension by Inducing BMPR2 Via IRF3," iScience, vol. 26, no. 2, article no. 105935, Cell Press, Feb 2023.
The definitive version is available at https://doi.org/10.1016/j.isci.2023.105935
Chemical and Biochemical Engineering
Keywords and Phrases
Biological Sciences; Cell Biology; Molecular Biology
International Standard Serial Number (ISSN)
Article - Journal
© 2023 The Authors, All rights reserved.
17 Feb 2023
National Institutes of Health, Grant HL103455