Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension

doi:10.15252/emmm.201404511

. 2015 Jun;7(6):695-713.

doi: 10.15252/emmm.201404511.

Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension

Kevin White¹, Yu Lu¹, Sofia Annis¹, Andrew E Hale¹, B Nelson Chau², James E Dahlman³, Craig Hemann⁴, Alexander R Opotowsky⁵, Sara O Vargas⁶, Ivan Rosas⁷, Mark A Perrella⁸, Juan C Osorio⁷, Kathleen J Haley⁷, Brian B Graham⁹, Rahul Kumar⁹, Rajan Saggar¹⁰, Rajeev Saggar¹¹, W Dean Wallace¹⁰, David J Ross¹⁰, Omar F Khan¹², Andrew Bader¹³, Bernadette R Gochuico¹⁴, Majed Matar¹⁵, Kevin Polach¹⁵, Nicolai M Johannessen¹⁶, Haydn M Prosser¹⁷, Daniel G Anderson³, Robert Langer³, Jay L Zweier⁴, Laurence A Bindoff¹⁸, David Systrom⁷, Aaron B Waxman⁷, Richard C Jin¹, Stephen Y Chan¹⁹

Affiliations

¹ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Regulus Therapeutics, San Diego, CA, USA.
³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ The Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
⁵ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁸ Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA.
¹⁰ Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Cardiothoracic Surgery, University of Arizona College of Medicine, Phoenix, AZ, USA.
¹² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁵ Celsion-EGEN, Inc., Huntsville, AL, USA.
¹⁶ Department of Cardiology, University of Bergen, Bergen, Norway.
¹⁷ The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
¹⁸ Department of Clinical Medicine, University of Bergen, Bergen, Norway Department of Neurology, Haukeland University Hospital, Bergen, Norway.
¹⁹ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA sychan@partners.org.

PMID: 25825391
PMCID: PMC4459813
DOI: 10.15252/emmm.201404511

Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension

Kevin White et al. EMBO Mol Med. 2015 Jun.

. 2015 Jun;7(6):695-713.

doi: 10.15252/emmm.201404511.

Authors

Affiliations

¹ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Regulus Therapeutics, San Diego, CA, USA.
³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ The Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
⁵ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁸ Division of Pulmonary/Critical Care Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO, USA.
¹⁰ Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Cardiothoracic Surgery, University of Arizona College of Medicine, Phoenix, AZ, USA.
¹² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁵ Celsion-EGEN, Inc., Huntsville, AL, USA.
¹⁶ Department of Cardiology, University of Bergen, Bergen, Norway.
¹⁷ The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
¹⁸ Department of Clinical Medicine, University of Bergen, Bergen, Norway Department of Neurology, Haukeland University Hospital, Bergen, Norway.
¹⁹ Divisions of Cardiovascular Medicine and Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA sychan@partners.org.

PMID: 25825391
PMCID: PMC4459813
DOI: 10.15252/emmm.201404511

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.

Keywords: endothelial; iron–sulfur; metabolism; microRNA; mitochondria.

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Figures

**Figure 1**
The miR-210-ISCU1/2 regulatory axis is activated in endothelium and remodeled vessels in PH
A RT–qPCR reveals that miR-210 was increased in lungs of mice with PH triggered by various conditions: *VHL*^−/− as compared with *VHL*^+/+ mice (N = 4/group), ***P < 0.0001 (first graph); hypoxia + SU5416 (Hyp + SU5416) (N = 6/group) as compared with normoxia + SU5416 (Norm + SU5416) (N = 7/group), **P = 0.0015 (second graph); *Il6* transgenic versus littermate control mice (N = 4/group), **P = 0.0097 (third graph); and *S. mansoni*-infected mice (N = 4) compared with non-infected control mice (N = 5), ***P < 0.0001 (fourth graph).
B From animal subjects in (A), *in situ* hybridization (ISH, purple stain) revealed increased miR-210 in < 100-μm pulmonary vessels of mice suffering from PH, *P = 0.0493 for first graph, **P = 0.0015 for second graph, *P = 0.0391 for third graph.
C Representative ISH stain of miR-210 in < 100 μm pulmonary vessels of mice (bottom micrographs) exposed to Hyp + SU5416 compared with Norm + SU5416 (α-smooth muscle actin stain from serial sections, top row of micrographs).
D Increased miR-210 in < 200-μm remodeled pulmonary vessels of patients suffering from PAH (N = 19, Supplementary Table S1) as compared with non-PAH donor control lung (N = 10). Serial staining with hematoxylin and eosin is displayed in the top row of micrographs; quantification of miRNA ISH, right graph, *P = 0.0167.
E Increased levels of miR-210 in plasma drawn from the pulmonary circulation (pulmonary capillary wedge position, PCWP) of patients with elevated mean pulmonary arterial pressures (mean PAP ≥ 25 mmHg) compared with control subjects (mPAP < 25 mmHg, N = 5/group, demographics in Supplementary Table S2), *P = 0.0357.
F, G From animals in (C) and humans in (D), immunohistochemistry (IHC) revealed that the miR-210 targets ISCU1/2 were reciprocally down-regulated in miR-210-enriched remodeled pulmonary vessels—namely in PH mice exposed to Hyp + SU5416 (F, ***P = 0.0002) and in human PAH patients (G, ***P = 0.0008).
H, I miR-210 expression (H) was increased (***P = 0.0003), and ISCU1/2 expression (I) was decreased (***P < 0.0001) in PECAM⁺ pulmonary vascular endothelial cells isolated from PH mice (Hyp + SU5416) as compared with control (Norm + SU5416) (N = 4/group, left bars).
Data information: In (A, B), mean expression of miR-210 in control groups was assigned a fold change of 1, to which all samples were compared. Error bars reflect SEM. Mouse tissue scale bar: 50 μm, human tissue scale bar: 100 μm.

**Figure 2**
Impaired Fe-S cluster integrity in diseased pulmonary vasculature is driven by the miR-210-ISCU1/2 axis
After lentiviral delivery of GCN4 or GRX2 sensor genes to human PAECs, cellular fluorescence was measured by flow cytometry. Unlike control GCN4 sensors that homodimerized independent of Fe-S levels and induced consistent fluorescence, fluorescence derived from the GRX2 Fe-S-dependent sensors decreased in hypoxia, as displayed in representative flow cytometric plots (left) and by quantification of percentage of positive cells [(cell number in M2 gate)/(total cell number) × 100]. Immunoblotting revealed consistent expression of either GRX2 or GCN4 sensors (FLAG-tagged) in hypoxia (Hyp) compared with normoxia (Norm) (N = 3, ***P < 0.0001 for GRX2; N = 3, NS P = 0.1848 for GCN4).
In contrast to consistent fluorescence from control GCN4 sensors, Fe-S-dependent GRX2 sensor fluorescence was decreased by siRNA knockdown of ISCU1/2 (siISCU) as compared with control (siCont) (N = 3, ***P < 0.0001 for GRX2; N = 3, NS P = 0.1790 for GCN4).
GRX2, but not GCN4, sensor fluorescence was decreased after transfection of miR-210 oligonucleotide mimic (miR-210) as compared with control (miRC) (N = 3, ***P = 0.0002 for GRX2; N = 3, NS P = 0.0913 for GCN4). During hypoxic exposure, GRX2, but not GCN4, sensor fluorescence was increased after transfection of an antisense miR-210 inhibitor (AS210) as compared with control (ASC) (N = 3, **P = 0.003 for GRX2; N = 3, NS P = 0.1194 for GCN4).
After lentiviral delivery of sensor genes, Fe-S-dependent GRX2 sensor fluorescence was decreased in PECAM-positive cells from PH mouse lung (Hyp + SU5416) as compared with control non-PH mouse lung (Norm + SU5416, N = 3, ***P < 0.001).
By electron paramagnetic resonance (EPR) spectroscopy (representative *VHL*^−/− versus control lung), Fe-S cluster signal was decreased (left graph) in *VHL*^−/− mice lung tissue (*VHL*^−/−, N = 3) as compared with WT control lung tissues (WT, N = 5), ***P = 0.0003.
By EPR, Fe-S-specific signal was decreased (right graph) in human PH-diseased lung tissue harvested at lung transplantation (PH, N = 3, Supplementary Table S3) compared with non-PH control donor lung tissues (control, N = 3), *P = 0.048.
Data information: In (A–C), sensor expression was confirmed by immunoblot for FLAG epitopes. Error bars reflect SEM. Source data are available online for this figure.

**Figure 3**
miR-210 regulates Fe-S biogenesis, mitochondrial function, and downstream PH pathways *in vivo* and is necessary to induce hypoxic PH in mice
A Schema of comparing *miR-210*^−/− and WT mice after hypoxia + SU5416 (PH) versus normoxia + SU5416 (control).
B By immunohistochemistry (IHC), ISCU1/2 was unchanged in < 100 μm pulmonary vessels of *miR-210*^−/− mice exposed to Hyp + SU5416 (N = 6) versus Norm + SU5416 (N = 7), NS P = 0.2833.
C Fe-S-dependent Complex I-specific activity was decreased in WT PH mice as compared with control (N = 7/group, left bars, ***P < 0.0001), but activity was preserved in the lungs of *miR-210*^−/− mice in either condition (N = 8/group, right bars), NS P = 0.3693.
D IHC demonstrated that pulmonary vascular GLUT1 was increased in WT PH mice (left bars, ***P = 0.0006), but GLUT1 was unchanged in *miR-210*^−/− mice in either condition (right bars, NS P = 0.9967).
E 3-nitrotyrosine (3-NT) was increased in pulmonary vessels of WT PH mice but was reduced in *miR-210*^−/− mice in either condition (N = 6/group) (***P < 0.0001, NS P = 0.4087).
F In PH conditions, endothelin-1 was decreased in *miR-210*^−/− lung tissue compared with WT tissue (N = 5/group), **P = 0.007.
G PCNA was increased in WT PH pulmonary vessels but was decreased in *miR-210*^−/− tissue exposed to either condition (N = 5/group) (**P = 0.0096, *P = 0.0124, *P = 0.0263 for *miR-210*^−/−).
H PCNA was increased in PECAM⁺ endothelial cells from PH versus non-PH mice (N = 3/group, **P = 0.0052).
I Unlike WT mice (black bars) demonstrating increased right ventricular systolic pressure (RVSP) after Hyp + SU5416 (N = 10) versus Norm + SU5416 (N = 11), hemodynamic dysregulation was significantly alleviated in *miR-210*^−/− mice (white bars, N = 11) (***P < 0.0001, *P = 0.0258, **P = 0.0059).
J Compared with WT controls (N = 9), *miR-210*^−/− mice (N = 8) displayed a blunted increase of the Fulton index (RV/LV + S) under PH versus baseline conditions (expressed as a ratio of RV/LV + S under Hyp + SU5416 versus Norm + SU5416, *P = 0.031).
K–M Under PH (black bars, N = 8/group) versus baseline conditions (white bars, N = 6/group), pulmonary vascular remodeling was alleviated in *miR-210*^−/− mice, as visualized via histology (L), and confirmed by decreased % arteriolar muscularization (K, **P = 0.001, **P = 0.0045 for *miR-210*^−/−, *P = 0.0158) and decreased vessel wall thickness (M, ***P < 0.0001, **P = 0.0086).
Data information: Error bars reflect SEM. Mouse tissue scale bar: 50 μm.

**Figure 4**
MiR-210 is sufficient to induce pulmonary vascular dysfunction in mice
A Schema for forced miR-210 expression *in vivo* (N = 8/group).
B, C Intrapharyngeal delivery of miR-210 mimic increased miR-210 in whole lung (***P = 0.0002) (B) and in < 100-μm pulmonary vessels (**P = 0.007) (C).
D miR-210 mimic also repressed ISCU1/2 levels in those same caliber vessels (N = 6/group), **P = 0.0022.
E Endothelin-1 was increased in mouse lung tissue after delivery of miR-210 mimic (N = 6/group), *P = 0.0368.
F–H miR-210 mimic delivery increased RVSP (N = 8/group) (F) and vascular remodeling (α-smooth muscle actin stain, α-SMA), as evidenced by increased percent of muscularized (< 100 μm) pulmonary vessels (G) and increased medial thickening relative to vessel diameter when compared with miR-Control (H) (N = 6/group). **P = 0.0021 for (F), **P = 0.0072 for (G), *P = 0.0335 for (H).
Data information: Error bars reflect SEM. Mouse tissue scale bar: 50 μm.

**Figure 5**
Antisense inhibition of miR-210 protects against and improves existing manifestations of PH *in vivo*
A Schema of the strategy to determine whether antisense inhibition of miR-210 (anti-miR-210) prevents PH secondary to Hyp + SU5416 exposure (“prevention protocol”).
B–D Intravenous delivery of anti-miR-210 down-regulated miR-210 expression in whole lung tissue (N = 7/group), ***P < 0.0001 (B), the pulmonary vasculature as assessed by *in situ* staining (N = 7/group), ***P = 0.0003 (C), and PECAM⁺ vascular endothelial cells derived from whole lung tissue (N = 4/group), **P = 0.0013 (D).
E Correspondingly, anti-miR-210 delivery resulted in preservation of ISCU1/2 expression in < 100-μm pulmonary vessels as compared to anti-miR-Control (N = 5/group), **P = 0.0011.
F Similarly, ISCU1/2 expression was preserved in PECAM⁺ endothelial cells derived from mice treated with anti-miR-210 (N = 4/group), **P = 0.0016.
G Endothelin-1 was decreased in lung tissue from mice treated with anti-miR-210 during Hyp + SU5416 exposure (N = 6/group), *P = 0.0181.
H As assessed by *in situ* immunofluorescence, PCNA was decreased in pulmonary vessels (< 100 μm) after anti-miR-210 delivery, **P = 0.001.
I–K Anti-miR-210 delivery (N = 10/group) ameliorated the elevation of RVSP, **P = 0.0031 (i) and vascular remodeling, as reflected by increased percent of muscularized arterioles (N = 8/group, **P = 0.0091) (J) and increased medial thickness relative to vessel diameter in < 100-μm pulmonary vessels (N = 6/group, **P = 0.0021) (K).
L Schema of the strategy to determine whether anti-miR-210 improves existing PH (“reversal protocol”).
M, N Pharmacologic inhibition of miR-210 (N = 7/group) down-regulated pulmonary expression of miR-210, ***P < 0.0001 (M), and preserved ISCU1/2 expression in < 100-μm pulmonary vessels, **P = 0.0015 (N).
O–Q In contrast to anti-miR-Control (N = 8), anti-miR-210 ameliorated the elevation of RVSP (N = 10/group, ***P < 0.0001) (O) and pulmonary vascular remodeling (N = 7/group, **P = 0.0022, *P = 0.0167) (P–Q).
Data information: Error bars reflect SEM. Mouse tissue scale bar: 50 μm.

**Figure 6**
Antisense inhibition of miR-210 specifically in vascular endothelium improves existing manifestations of PH *in vivo*
A Following the schema of Fig5A in the presence of hypoxia but the absence of SU5416, intravenous delivery of anti-miR-210 ameliorated the elevation of RVSP compared with anti-miR-Control (N = 6/group, ***P = 0.001).
B Schema of the strategy to determine whether delivery of anti-miR-210 specifically to the vascular endothelium via packaging with 7C1 nanoparticles improves hypoxia-induced PH (“7C1 reversal protocol”).
C, D Consistent with specific delivery to the vascular endothelium after intravenous administration (Dahlman *et al*, 2014), 7C1-mediated delivery of anti-miR-210 (N = 6/group) decreased miR-210 expression in PECAM⁺ pulmonary vascular endothelial cells, **P = 0.0013, (D) but not PECAM-negative pulmonary cells, NS P = 0.3775 (C).
E Correspondingly, endothelial-specific anti-miR-210 (N = 6/group) increased ISCU1/2 expression in PECAM⁺ cells even in the presence of chronic hypoxia, ***P = 0.0003.
F–I Delivery of anti-miR-210 (N = 5/group) decreased endothelin-1 in hypoxic mouse lung tissue, *P = 0.0198 (F). As a result, in contrast to anti-miR-Control (N = 8), endothelial-specific anti-miR-210 ameliorated the elevation of RVSP (N = 6), **P = 0.0024 (G), and pulmonary vascular remodeling (N = 6/group), **P = 0.0021, *P = 0.0117 (H–I).
Data information: Error bars reflect SEM. Mouse tissue scale bar: 50 μm.

**Figure 7**
siRNA knockdown of pulmonary vascular ISCU1/2 *in vivo* promotes PH
A Schema of the strategy for pharmacologic inhibition of siRNA knockdown of ISCU1/2 in the pulmonary vasculature of mice *in vivo* by Staramine-mPEG-mediated intravenous delivery.
B, C Pharmacologic inhibition of ISCU (N = 8/group) did not influence miR-210 expression in the lungs either after Norm + SU5415, NS P = 0.8634 (B) or Hyp + SU5416, NS P = 0.9786 (C).
D As compared with control siRNA (siCont) where ISCU1/2 expression was decreased after exposure to Hyp + SU5416 (white bars), pulmonary vascular delivery of siRNA specific for ISCU1/2 (siISCU) via Staramine-mPEG nanocomplexes (Polach *et al*, 2012) down-regulated ISCU1/2 in < 100-μm pulmonary vessels in Norm + SU5416 and Hyp + SU5416 (N = 5/group, ***P = 0.0006, **P = 0.0019 for Hyp + SU5416, **P = 0.0029 for siCont).
E By electron paramagnetic resonance (EPR) spectroscopy (representative siCont versus siISCU lung), Fe-S cluster signal was decreased (quantitative graph, right) in siISCU mouse lung tissue (N = 4 mice) compared with siCont (N = 5 mice), *P = 0.0143.
F Endothelin-1 was increased in lung tissue after siISCU delivery under normoxic conditions (N = 5/group), **P = 0.0027.
G–I In the absence (left bars) and presence (right bars) of Hyp + SU5416 for 2 weeks, siISCU (black bars) induced elevations in RVSP (***P < 0.0001, **P = 0.0031) (G) and increased pulmonary vascular remodeling in < 100-μm pulmonary vessels (H, I) as compared with siCont (N = 5/group, ***P = 0.0003, *P = 0.0114 for H; ***P = 0.0006, **P = 0.0098 for I).
J Model of acquired and genetic Fe-S deficiency as a central cause of metabolic dysfunction and PH in mice and humans. Among others, potential translational implications are highlighted in red text.
Data information: Error bars reflect SEM. Mouse tissue scale bar: 50 μm.

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Comment in

New insights into the pathology of pulmonary hypertension: implication of the miR-210/ISCU1/2/Fe-S axis.
Tang H, Ayon RJ, Yuan JX. Tang H, et al. EMBO Mol Med. 2015 Jun;7(6):689-91. doi: 10.15252/emmm.201505160. EMBO Mol Med. 2015. PMID: 25851536 Free PMC article.

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References

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1. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55–S66. - PubMed
1. Barclay AR, Sholler G, Christodolou J, Shun A, Arbuckle S, Dorney S, Stormon MO. Pulmonary hypertension–a new manifestation of mitochondrial disease. J Inherit Metab Dis. 2005;28:1081–1089. - PubMed
1. Beinert H, Holm RH, Munck E. Iron–sulfur clusters: nature's modular, multipurpose structures. Science. 1997;277:653–659. - PubMed
1. Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest. 2014;124:3514–3528. - PMC - PubMed

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[1] Argiento P, Vanderpool RR, Mule M, Russo MG, D'Alto M, Bossone E, Chesler NC, Naeije R. Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences. Chest. 2012;142:1158–1165. - PMC - PubMed

[2] Argiento P, Vanderpool RR, Mule M, Russo MG, D'Alto M, Bossone E, Chesler NC, Naeije R. Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences. Chest. 2012;142:1158–1165. - PMC - PubMed

[3] Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55–S66. - PubMed

[4] Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55–S66. - PubMed

[5] Barclay AR, Sholler G, Christodolou J, Shun A, Arbuckle S, Dorney S, Stormon MO. Pulmonary hypertension–a new manifestation of mitochondrial disease. J Inherit Metab Dis. 2005;28:1081–1089. - PubMed

[6] Barclay AR, Sholler G, Christodolou J, Shun A, Arbuckle S, Dorney S, Stormon MO. Pulmonary hypertension–a new manifestation of mitochondrial disease. J Inherit Metab Dis. 2005;28:1081–1089. - PubMed

[7] Beinert H, Holm RH, Munck E. Iron–sulfur clusters: nature's modular, multipurpose structures. Science. 1997;277:653–659. - PubMed

[8] Beinert H, Holm RH, Munck E. Iron–sulfur clusters: nature's modular, multipurpose structures. Science. 1997;277:653–659. - PubMed

[9] Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest. 2014;124:3514–3528. - PMC - PubMed

[10] Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest. 2014;124:3514–3528. - PMC - PubMed

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Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension

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Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension

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