dc.contributor.author | White, Kevin | en_US |
dc.contributor.author | Lu, Yu | en_US |
dc.contributor.author | Annis, Sofia | en_US |
dc.contributor.author | Hale, Andrew E. | en_US |
dc.contributor.author | Chau, B. Nelson | en_US |
dc.contributor.author | Dahlman, James E. | en_US |
dc.contributor.author | Hemann, Craig | en_US |
dc.contributor.author | Opotowsky, Alexander R. | en_US |
dc.contributor.author | Vargas, Sara O. | en_US |
dc.contributor.author | Rosas, Ivan | en_US |
dc.contributor.author | Perrella, Mark A. | en_US |
dc.contributor.author | Osorio, Juan C. | en_US |
dc.contributor.author | Haley, Kathleen J. | en_US |
dc.contributor.author | Graham, Brian B. | en_US |
dc.contributor.author | Kumar, Rahul | en_US |
dc.contributor.author | Saggar, Rajan | en_US |
dc.contributor.author | Saggar, Rajeev | en_US |
dc.contributor.author | Wallace, W. Dean | en_US |
dc.contributor.author | Ross, David J. | en_US |
dc.contributor.author | Khan, Omar F. | en_US |
dc.contributor.author | Bader, Andrew | en_US |
dc.contributor.author | Gochuico, Bernadette R. | en_US |
dc.contributor.author | Matar, Majed | en_US |
dc.contributor.author | Polach, Kevin | en_US |
dc.contributor.author | Johannessen, Nicolai | en_US |
dc.contributor.author | Prosser, Haydn M. | en_US |
dc.contributor.author | Anderson, Daniel G. | en_US |
dc.contributor.author | Langer, Robert | en_US |
dc.contributor.author | Zweier, Jay L. | en_US |
dc.contributor.author | Bindoff, Laurence | en_US |
dc.contributor.author | Systrom, David | en_US |
dc.contributor.author | Waxman, Aaron B. | en_US |
dc.contributor.author | Jin, Richard C. | en_US |
dc.contributor.author | Chan, Stephen Y. | en_US |
dc.date.accessioned | 2016-03-14T12:10:07Z | |
dc.date.available | 2016-03-14T12:10:07Z | |
dc.date.issued | 2015 | |
dc.Published | EMBO Molecular Medicine 2015, 7(6):695-713 | eng |
dc.identifier.issn | 1757-4684 | |
dc.identifier.uri | https://hdl.handle.net/1956/11632 | |
dc.description.abstract | Iron–sulfur (Fe‐S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR‐210‐ISCU1/2 axis cause Fe‐S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR‐210 and repression of the miR‐210 targets ISCU1/2 down‐regulated Fe‐S levels. In mouse and human vascular and endothelial tissue affected by PH, miR‐210 was elevated accompanied by decreased ISCU1/2 and Fe‐S integrity. In mice, miR‐210 repressed ISCU1/2 and promoted PH. Mice deficient in miR‐210, via genetic/pharmacologic means or via an endothelial‐specific manner, displayed increased ISCU1/2 and were resistant to Fe‐S‐dependent pathophenotypes and PH. Similar to hypoxia or miR‐210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR‐210‐ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe‐S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings. | en_US |
dc.language.iso | eng | eng |
dc.publisher | EMBO Press | eng |
dc.rights | Attribution CC BY | eng |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0 | eng |
dc.subject | endothelial | eng |
dc.subject | iron–sulfur | eng |
dc.subject | metabolism | eng |
dc.subject | microRNA | eng |
dc.subject | mitochondria | eng |
dc.title | Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension | en_US |
dc.type | Peer reviewed | |
dc.type | Journal article | |
dc.date.updated | 2015-12-29T14:31:10Z | |
dc.description.version | publishedVersion | en_US |
dc.rights.holder | Copyright 2015 The Authors | |
dc.identifier.doi | https://doi.org/10.15252/emmm.201404511 | |
dc.identifier.cristin | 1254465 | |
dc.subject.nsi | VDP::Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Generell patologi, patologisk anatomi : 719 | |
dc.subject.nsi | VDP::Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::General pathology, anatomical pathology: 719 | |
dc.subject.nsi | VDP::Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 | |
dc.subject.nsi | VDP::Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 | |