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 M | 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 A | 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 | 2015-07-13T18:47:22Z | |
dc.date.issued | 2015 | en_US |
dc.identifier.citation | White, K., Y. Lu, S. Annis, A. E. Hale, B. N. Chau, J. E. Dahlman, C. Hemann, et al. 2015. “Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension.” EMBO Molecular Medicine 7 (6): 695-713. doi:10.15252/emmm.201404511. http://dx.doi.org/10.15252/emmm.201404511. | en |
dc.identifier.issn | 1757-4676 | en |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295703 | |
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 |
dc.language.iso | en_US | en |
dc.publisher | BlackWell Publishing Ltd | en |
dc.relation.isversionof | doi:10.15252/emmm.201404511 | en |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459813/pdf/ | en |
dash.license | LAA | en_US |
dc.subject | endothelial | en |
dc.subject | iron–sulfur | en |
dc.subject | metabolism | en |
dc.subject | microRNA | en |
dc.subject | mitochondria | en |
dc.title | Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension | en |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en |
dc.relation.journal | EMBO Molecular Medicine | en |
dash.depositing.author | Lu, Yu | en_US |
dc.date.available | 2015-07-13T18:47:22Z | |
dc.identifier.doi | 10.15252/emmm.201404511 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Opotowsky, Alexander | |
dash.contributor.affiliated | Systrom, David | |
dash.contributor.affiliated | Chan, Stephen Y | |
dash.contributor.affiliated | Lu, Yu | |
dash.contributor.affiliated | Vargas, Sara | |
dash.contributor.affiliated | Waxman, Aaron | |
dash.contributor.affiliated | Rosas, Ivan | |
dash.contributor.affiliated | Haley, Kathleen | |
dash.contributor.affiliated | Perrella, Mark | |
dash.contributor.affiliated | Anderson, Daniel | |
dash.contributor.affiliated | Langer, Robert | |