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Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension
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 a...
| Autores principales: | , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
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Nature Publishing Group UK
2023
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663616/ https://www.ncbi.nlm.nih.gov/pubmed/37989727 http://dx.doi.org/10.1038/s41467-023-43039-y |
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| author | Isobe, Sarasa Nair, Ramesh V. Kang, Helen Y. Wang, Lingli Moonen, Jan-Renier Shinohara, Tsutomu Cao, Aiqin Taylor, Shalina Otsuki, Shoichiro Marciano, David P. Harper, Rebecca L. Adil, Mir S. Zhang, Chongyang Lago-Docampo, Mauro Körbelin, Jakob Engreitz, Jesse M. Snyder, Michael P. Rabinovitch, Marlene |
| author_facet | Isobe, Sarasa Nair, Ramesh V. Kang, Helen Y. Wang, Lingli Moonen, Jan-Renier Shinohara, Tsutomu Cao, Aiqin Taylor, Shalina Otsuki, Shoichiro Marciano, David P. Harper, Rebecca L. Adil, Mir S. Zhang, Chongyang Lago-Docampo, Mauro Körbelin, Jakob Engreitz, Jesse M. Snyder, Michael P. Rabinovitch, Marlene |
| author_sort | Isobe, Sarasa |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-10663616 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2023 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-106636162023-11-21 Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension Isobe, Sarasa Nair, Ramesh V. Kang, Helen Y. Wang, Lingli Moonen, Jan-Renier Shinohara, Tsutomu Cao, Aiqin Taylor, Shalina Otsuki, Shoichiro Marciano, David P. Harper, Rebecca L. Adil, Mir S. Zhang, Chongyang Lago-Docampo, Mauro Körbelin, Jakob Engreitz, Jesse M. Snyder, Michael P. Rabinovitch, Marlene Nat Commun Article 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. Nature Publishing Group UK 2023-11-21 /pmc/articles/PMC10663616/ /pubmed/37989727 http://dx.doi.org/10.1038/s41467-023-43039-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
| spellingShingle | Article Isobe, Sarasa Nair, Ramesh V. Kang, Helen Y. Wang, Lingli Moonen, Jan-Renier Shinohara, Tsutomu Cao, Aiqin Taylor, Shalina Otsuki, Shoichiro Marciano, David P. Harper, Rebecca L. Adil, Mir S. Zhang, Chongyang Lago-Docampo, Mauro Körbelin, Jakob Engreitz, Jesse M. Snyder, Michael P. Rabinovitch, Marlene Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension |
| title | Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension |
| title_full | Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension |
| title_fullStr | Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension |
| title_full_unstemmed | Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension |
| title_short | Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension |
| title_sort | reduced foxf1 links unrepaired dna damage to pulmonary arterial hypertension |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663616/ https://www.ncbi.nlm.nih.gov/pubmed/37989727 http://dx.doi.org/10.1038/s41467-023-43039-y |
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