iScience (Feb 2023)
A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3
- Aneel R. Bhagwani,
- Mehboob Ali,
- Bryce Piper,
- Mingjun Liu,
- Jaylen Hudson,
- Neil Kelly,
- Srimathi Bogamuwa,
- Hu Yang,
- James D. Londino,
- Joseph S. Bednash,
- Daniela Farkas,
- Rama K. Mallampalli,
- Mark R. Nicolls,
- John J. Ryan,
- A.A. Roger Thompson,
- Stephen Y. Chan,
- Delphine Gomez,
- Elena A. Goncharova,
- Laszlo Farkas
Affiliations
- Aneel R. Bhagwani
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Mehboob Ali
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Bryce Piper
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Mingjun Liu
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Jaylen Hudson
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Neil Kelly
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Srimathi Bogamuwa
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Hu Yang
- Chemical & Biochemical Engineering, Missouri S&T, Rolla, MO 65409, USA
- James D. Londino
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Joseph S. Bednash
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Daniela Farkas
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Rama K. Mallampalli
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Mark R. Nicolls
- VA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University School of Medicine, Stanford, CA 94305, USA
- John J. Ryan
- College of Humanities & Sciences, Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
- A.A. Roger Thompson
- Department of Infection, Immunity & Cardiovascular Disease, Faculty of Medicine, Dentistry & Health, University of Sheffield, Sheffield S10 2RX, UK
- Stephen Y. Chan
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Delphine Gomez
- Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Elena A. Goncharova
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, University of California Davis, Davis, CA 95616, USA
- Laszlo Farkas
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 2
p. 105935
Abstract
Summary: 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.
