Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Sarasa Isobe; Ramesh V. Nair; Helen Y. Kang; Lingli Wang; Jan-Renier Moonen; Tsutomu Shinohara; Aiqin Cao; Shalina Taylor; Shoichiro Otsuki; David P. Marciano; Rebecca L. Harper; Mir S. Adil; Chongyang Zhang; Mauro Lago-Docampo; Jakob Körbelin; Jesse M. Engreitz; Michael P. Snyder; Marlene Rabinovitch

doi:10.1038/s41467-023-43039-y

Nature Communications (Nov 2023)

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Sarasa Isobe,
Ramesh V. Nair,
Helen Y. Kang,
Lingli Wang,
Jan-Renier Moonen,
Tsutomu Shinohara,
Aiqin Cao,
Shalina Taylor,
Shoichiro Otsuki,
David P. Marciano,
Rebecca L. Harper,
Mir S. Adil,
Chongyang Zhang,
Mauro Lago-Docampo,
Jakob Körbelin,
Jesse M. Engreitz,
Michael P. Snyder,
Marlene Rabinovitch

Affiliations

Sarasa Isobe: 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
Ramesh V. Nair: Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine
Helen Y. Kang: 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
Lingli Wang: 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
Jan-Renier Moonen: 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
Tsutomu Shinohara: 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
Aiqin Cao: 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
Shalina Taylor: Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University
Shoichiro Otsuki: Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University
David P. Marciano: Stanford Cardiovascular Institute, Stanford University School of Medicine
Rebecca L. Harper: Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University
Mir S. Adil: 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
Chongyang Zhang: 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
Mauro Lago-Docampo: 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
Jakob Körbelin: Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf
Jesse M. Engreitz: 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
Michael P. Snyder: Stanford Cardiovascular Institute, Stanford University School of Medicine
Marlene Rabinovitch: 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

DOI: https://doi.org/10.1038/s41467-023-43039-y
Journal volume & issue: Vol. 14, no. 1
pp. 1 – 18

Abstract

Read online

Abstract 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.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

About the journal