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

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Nat Commun. 2023 Nov 21;14(1):7578. doi: 10.1038/s41467-023-43039-y.

Authors

Sarasa Isobe^{1

2

3

4}, Ramesh V Nair⁵, Helen Y Kang^{1

6}, Lingli Wang^{1

2

3

4}, Jan-Renier Moonen^{1

2

3

4}, Tsutomu Shinohara^{1

2

3

4}, Aiqin Cao^{1

2

3

4}, Shalina Taylor^{2

3

4}, Shoichiro Otsuki^{2

3

4}, David P Marciano^{3

6}, Rebecca L Harper^{2

3

4}, Mir S Adil^{1

2

3

4}, Chongyang Zhang^{1

2

3

4}, Mauro Lago-Docampo^{1

2

3

4}, Jakob Körbelin⁷, Jesse M Engreitz^{1

3

6}, Michael P Snyder^{3

6}, Marlene Rabinovitch^{8

9

10

11}

Affiliations

¹ 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.
² Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.
³ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸ 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. [email protected].
⁹ Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA. [email protected].
¹⁰ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹¹ Department of Pediatrics - Cardiology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].

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.

MeSH terms

Animals
Bone Morphogenetic Protein Receptors, Type II / genetics
DNA Damage
Familial Primary Pulmonary Hypertension / metabolism
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Humans
Hypertension, Pulmonary* / genetics
Hypertension, Pulmonary* / metabolism
Mice
Pulmonary Arterial Hypertension* / genetics
Pulmonary Artery / metabolism

Substances

Bone Morphogenetic Protein Receptors, Type II
Forkhead Transcription Factors
FOXF1 protein, human

Abstract

MeSH terms

Substances

Grants and funding