Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension.

Autor: Isobe S; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Nair RV; Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA., Kang HY; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Wang L; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Moonen JR; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Shinohara T; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Cao A; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Taylor S; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Otsuki S; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Marciano DP; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Harper RL; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Adil MS; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Zhang C; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Lago-Docampo M; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA., Körbelin J; Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Engreitz JM; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Snyder MP; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Rabinovitch M; Basic Science and Engineering (BASE) Initiative at the Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA. marlener@stanford.edu.; Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA. marlener@stanford.edu.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. marlener@stanford.edu.; Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA. marlener@stanford.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Nov 21; Vol. 14 (1), pp. 7578. Date of Electronic Publication: 2023 Nov 21.
DOI: 10.1038/s41467-023-43039-y
Abstrakt: Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2 -/- ) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm -/- ). Gene expression analysis of EC-Atm -/- and EC-Bmpr2 -/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2 -/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.
(© 2023. The Author(s).)
Databáze: MEDLINE
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