1. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension.
- Author
-
White, Kevin, Lu, Yu, Annis, Sofia, Hale, Andrew E, Chau, B Nelson, Dahlman, James E, Hemann, Craig, Opotowsky, Alexander R, Vargas, Sara O, Rosas, Ivan, Perrella, Mark A, Osorio, Juan C, Haley, Kathleen J, Graham, Brian B, Kumar, Rahul, Saggar, Rajan, Saggar, Rajeev, Wallace, W Dean, Ross, David J, Khan, Omar F, Bader, Andrew, Gochuico, Bernadette R, Matar, Majed, Polach, Kevin, Johannessen, Nicolai M, Prosser, Haydn M, Anderson, Daniel G, Langer, Robert, Zweier, Jay L, Bindoff, Laurence A, Systrom, David, Waxman, Aaron B, Jin, Richard C, and Chan, Stephen Y
- Subjects
Cells ,Cultured ,Endothelial Cells ,Animals ,Humans ,Mice ,Hypertension ,Pulmonary ,Genetic Predisposition to Disease ,Sulfur ,Iron ,Iron-Sulfur Proteins ,MicroRNAs ,Female ,Hypoxia ,endothelial ,iron–sulfur ,metabolism ,microRNA ,mitochondria ,iron-sulfur ,Cells ,Cultured ,Hypertension ,Pulmonary ,Biological Sciences ,Medical and Health Sciences - 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.
- Published
- 2015