| First Author | Bhagwani AR | Year | 2023 |
| Journal | iScience | Volume | 26 |
| Issue | 2 | Pages | 105935 |
| PubMed ID | 36685041 | Mgi Jnum | J:336244 |
| Mgi Id | MGI:7430482 | Doi | 10.1016/j.isci.2023.105935 |
| Citation | Bhagwani AR, et al. (2023) A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3. iScience 26(2):105935 |
| abstractText | 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. |
