IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-43039-y.html
   My bibliography  Save this article

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Author

Listed:
  • Sarasa Isobe

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Ramesh V. Nair

    (Stanford University School of Medicine)

  • Helen Y. Kang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Lingli Wang

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Jan-Renier Moonen

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Tsutomu Shinohara

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Aiqin Cao

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Shalina Taylor

    (Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Shoichiro Otsuki

    (Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • David P. Marciano

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Rebecca L. Harper

    (Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Mir S. Adil

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Chongyang Zhang

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Mauro Lago-Docampo

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Jakob Körbelin

    (University Medical Center Hamburg-Eppendorf)

  • Jesse M. Engreitz

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Michael P. Snyder

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Marlene Rabinovitch

    (Stanford University School of Medicine
    Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine)

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.

Suggested Citation

  • 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. Adi, 2023. "Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43039-y
    DOI: 10.1038/s41467-023-43039-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43039-y
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-43039-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
    2. Yuhua Wang & Ram Naresh Pandey & Allen J. York & Jaya Mallela & William C. Nichols & Yueh-Chiang Hu & Jeffery D. Molkentin & Kathryn A. Wikenheiser-Brokamp & Rashmi S. Hegde, 2019. "The EYA3 tyrosine phosphatase activity promotes pulmonary vascular remodeling in pulmonary arterial hypertension," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    3. Bin-Bing S. Zhou & Stephen J. Elledge, 2000. "The DNA damage response: putting checkpoints in perspective," Nature, Nature, vol. 408(6811), pages 433-439, November.
    4. Tianying Su & Geoff Stanley & Rahul Sinha & Gaetano D’Amato & Soumya Das & Siyeon Rhee & Andrew H. Chang & Aruna Poduri & Brian Raftrey & Thanh Theresa Dinh & Walter A. Roper & Guang Li & Kelsey E. Qu, 2018. "Single-cell analysis of early progenitor cells that build coronary arteries," Nature, Nature, vol. 559(7714), pages 356-362, July.
    5. Astrid Gillich & Fan Zhang & Colleen G. Farmer & Kyle J. Travaglini & Serena Y. Tan & Mingxia Gu & Bin Zhou & Jeffrey A. Feinstein & Mark A. Krasnow & Ross J. Metzger, 2020. "Capillary cell-type specialization in the alveolus," Nature, Nature, vol. 586(7831), pages 785-789, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yu Zhao & Yueqing Zhou & Weipan Zhang & Mingzhe Liu & Jun Duan & Xiaopeng Zhang & Qiwang Ma & Yujia Wang & Yuzhen Zhang & Zhongliang Guo & Ting Zhang & Wei Zuo, 2025. "Cloned airway basal progenitor cells to repair fibrotic lung through re-epithelialization," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    2. Niina M. Santio & Keerthana Ganesh & Pihla P. Kaipainen & Aleksi Halme & Fatemeh Seyednasrollah & Emad Arbash & Satu Hänninen & Riikka Kivelä & Olli Carpen & Pipsa Saharinen, 2024. "Endothelial Pim3 kinase protects the vascular barrier during lung metastasis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Qiang Zhang & Sai Ma & Zhengzhi Liu & Bohan Zhu & Zirui Zhou & Gaoshan Li & J. Javier Meana & Javier González-Maeso & Chang Lu, 2023. "Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Agnieska Brazovskaja & Tomás Gomes & Rene Holtackers & Philipp Wahle & Christiane Körner & Zhisong He & Theresa Schaffer & Julian Connor Eckel & René Hänsel & Malgorzata Santel & Makiko Seimiya & Timm, 2024. "Cell atlas of the regenerating human liver after portal vein embolization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Reza Mirzazadeh & Zaneta Andrusivova & Ludvig Larsson & Phillip T. Newton & Leire Alonso Galicia & Xesús M. Abalo & Mahtab Avijgan & Linda Kvastad & Alexandre Denadai-Souza & Nathalie Stakenborg & Ale, 2023. "Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Yuma Takano & Jun Suzuki & Kotaro Nomura & Gento Fujii & Junko Zenkoh & Hitomi Kawai & Yuta Kuze & Yukie Kashima & Satoi Nagasawa & Yuka Nakamura & Motohiro Kojima & Katsuya Tsuchihara & Masahide Seki, 2024. "Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Ahmed A. Raslan & Tho X. Pham & Jisu Lee & Konstantinos Kontodimas & Andrew Tilston-Lunel & Jillian Schmottlach & Jeongmin Hong & Taha Dinc & Andreea M. Bujor & Nunzia Caporarello & Aude Thiriot & Ulr, 2024. "Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    9. Gregory Farber & Yanhan Dong & Qiaozi Wang & Mitesh Rathod & Haofei Wang & Michelle Dixit & Benjamin Keepers & Yifang Xie & Kendall Butz & William J. Polacheck & Jiandong Liu & Li Qian, 2024. "Direct conversion of cardiac fibroblasts into endothelial-like cells using Sox17 and Erg," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Hongru Hu & Gerald Quon, 2024. "scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    11. Shixuan Liu & Camille Ezran & Michael F. Z. Wang & Zhengda Li & Kyle Awayan & Jonathan Z. Long & Iwijn De Vlaminck & Sheng Wang & Jacques Epelbaum & Christin S. Kuo & Jérémy Terrien & Mark A. Krasnow , 2024. "An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    12. Zhoufeng Wang & Zhe Li & Kun Zhou & Chengdi Wang & Lili Jiang & Li Zhang & Ying Yang & Wenxin Luo & Wenliang Qiao & Gang Wang & Yinyun Ni & Shuiping Dai & Tingting Guo & Guiyi Ji & Minjie Xu & Yiying , 2021. "Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    13. Christopher J. Hanley & Sara Waise & Matthew J. Ellis & Maria A. Lopez & Wai Y. Pun & Julian Taylor & Rachel Parker & Lucy M. Kimbley & Serena J. Chee & Emily C. Shaw & Jonathan West & Aiman Alzetani , 2023. "Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Eran Mick & Alexandra Tsitsiklis & Natasha Spottiswoode & Saharai Caldera & Paula Hayakawa Serpa & Angela M. Detweiler & Norma Neff & Angela Oliveira Pisco & Lucy M. Li & Hanna Retallack & Kalani Ratn, 2022. "Upper airway gene expression shows a more robust adaptive immune response to SARS-CoV-2 in children," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    15. Nicholas W. Chavkin & Gael Genet & Mathilde Poulet & Erin D. Jeffery & Corina Marziano & Nafiisha Genet & Hema Vasavada & Elizabeth A. Nelson & Bipul R. Acharya & Anupreet Kour & Jordon Aragon & Steph, 2022. "Endothelial cell cycle state determines propensity for arterial-venous fate," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Xue Gao & Sheng Wang & Yan-Fen Wang & Shuang Li & Shi-Xin Wu & Rong-Ge Yan & Yi-Wen Zhang & Rui-Dong Wan & Zhen He & Ren-De Song & Xin-Quan Zhao & Dong-Dong Wu & Qi-En Yang, 2022. "Long read genome assemblies complemented by single cell RNA-sequencing reveal genetic and cellular mechanisms underlying the adaptive evolution of yak," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Ronja Mothes & Anna Pascual-Reguant & Ralf Koehler & Juliane Liebeskind & Alina Liebheit & Sandy Bauherr & Lars Philipsen & Carsten Dittmayer & Michael Laue & Regina Manitius & Sefer Elezkurtaj & Pawe, 2023. "Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    18. Mayra Cruz Tleugabulova & Sandra P. Melo & Aaron Wong & Alexander Arlantico & Meizi Liu & Joshua D. Webster & Julia Lau & Antonie Lechner & Basak Corak & Jonathan J. Hodgins & Venkata S. Garlapati & M, 2024. "Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    19. Igor O. Shmarakov & Galina A. Gusarova & Mohammad N. Islam & María Marhuenda-Muñoz & Jahar Bhattacharya & William S. Blaner, 2023. "Retinoids stored locally in the lung are required to attenuate the severity of acute lung injury in male mice," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    20. Qizhou Lian & Kui Zhang & Zhao Zhang & Fuyu Duan & Liyan Guo & Weiren Luo & Bobo Wing-Yee Mok & Abhimanyu Thakur & Xiaoshan Ke & Pedram Motallebnejad & Vlad Nicolaescu & Jonathan Chen & Chui Yan Ma & , 2022. "Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43039-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.