Genetic and hypoxic alterations of the micro RNA ‐210‐ ISCU 1/2 axis promote iron–sulfur deficiency and pulmonary hypertension
| العنوان: | Genetic and hypoxic alterations of the micro |
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| المؤلفون: | Mark A. Perrella, David J. Ross, Ivan O. Rosas, Rajesh Kumar, Brian B. Graham, Kevin P. White, Daniel G. Anderson, Sara O. Vargas, Rajeev Saggar, Omar F. Khan, Kevin J. Polach, Alexander R. Opotowsky, Rajan Saggar, Aaron B. Waxman, Kathleen J. Haley, Stephen Y. Chan, Majed Matar, James E. Dahlman, Bernadette R. Gochuico, Andrew Bader, Richard C Jin, Sofia Annis, David M. Systrom, W. Dean Wallace, Nicolai M. Johannessen, Robert Langer, Jay L. Zweier, B. Nelson Chau, Laurence A. Bindoff, Andrew E. Hale, Juan C. Osorio, Haydn M. Prosser, Craig Hemann, Yu Lu |
| المساهمون: | Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Dahlman, James E., Bader, Andrew, Anderson, Daniel Griffith, Langer, Robert |
| المصدر: | EMBO molecular medicine, vol 7, iss 6 Wiley Blackwell |
| بيانات النشر: | EMBO, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Iron-Sulfur Proteins, Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Generell patologi, patologisk anatomi : 719 [VDP], iron-sulfur, 030204 cardiovascular system & hematology, Mitochondrion, Cardiovascular, Medical and Health Sciences, Mice, 0302 clinical medicine, Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], 2.1 Biological and endogenous factors, Hypoxia, Lung, 0303 health sciences, Gene knockdown, Cultured, microRNA, Pulmonary, Iron Deficiencies, Biological Sciences, 3. Good health, mitochondria, medicine.anatomical_structure, Biochemistry, Hypertension, Molecular Medicine, Female, medicine.symptom, medicine.medical_specialty, Endothelium, Iron, Cells, Biology, 03 medical and health sciences, Internal medicine, endothelial, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Psychological repression, iron–sulfur, 030304 developmental biology, Endothelial Cells, Metabolism, Hypoxia (medical), medicine.disease, Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::General pathology, anatomical pathology: 719 [VDP], Pulmonary hypertension, Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], MicroRNAs, Endocrinology, biology.protein, ISCU, metabolism, Sulfur |
| الوصف: | 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. National Institutes of Health (U.S.) (U54‐CA151884) National Institutes of Health (U.S.) (R01‐DE016516‐06) National Institutes of Health (U.S.) (EB000244) |
| وصف الملف: | application/pdf |
| تدمد: | 1757-4684 1757-4676 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::22a7eac69bbeee454e28b7e295367fd8Test https://doi.org/10.15252/emmm.201404511Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....22a7eac69bbeee454e28b7e295367fd8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17574684 17574676 |
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