Evidence map›Paper›PMID 25001622›Full record

ArticleCirculation2014

Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis.

Bradley A Maron, William M Oldham, Stephen Y Chan, Sara O Vargas, Elena Arons, Ying-Yi Zhang, Joseph Loscalzo, Jane A Leopold

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
48citing papers in PubMed, 1 pooled it
3.9field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

48 citing papers in PubMed, 1 synthesis or guideline pooled it, 67 citations in OpenAlex.

  1. Meta-analysis of blood genome-wide expression profiling studies in pulmonary arterial hypertension.American journal of physiology. Lung cellular and molecular physiology · 2020
    Pooled it
  2. Article
  3. Article
  4. Review
  5. Efficacy of spironolactone in pulmonary arterial hypertension.Hypertension research : official journal of the Japanese Society of Hypertension · 2025
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 1 institution in 1 country.

Bradley A MaronFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.). bmaron@partners.org.
William M OldhamFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).
Stephen Y ChanFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).
Sara O VargasFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).
Elena AronsFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).
Ying-Yi ZhangFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).
Joseph LoscalzoFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).
Jane A LeopoldFrom the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA (S.O.V.).
VA Boston Healthcare System · US

Funding

Tissue AnalysesP01HL048743 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LIBBY, PETER · 1992 to 2014
$26.3M
RESPIRATORY RESEARCHT32HL007633 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI George R Washko · 1985 to 2026
$14.9M
Single Molecule Analysis of Sickle Erythrocyte Adhesion in Sickle Cell DiseaseU54HL070819 · NHLBI · BOSTON MEDICAL CENTER · PI LEOPOLD, JANE A · 2003 to 2011
$12.5M
GPx-3 and Peroxide Flux in the Endothelial CellR37HL061795 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LOSCALZO, JOSEPH · 2007 to 2016
$4.3M
Targeting FAK-NEDD9 protein-protein interaction to prevent focal adhesion assembly and vascular proliferation in pulmonary arterial hypertensionR01HL139613 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI Sirano Dhe-Paganon, Bradley Maron · 2018 to 2026
$4.1M
The Phathophenotype Landscape of Complex DiseaseU01HL108630 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LOSCALZO, JOSEPH · 2011 to 2014
$2.7M
Aldosterone, Autophagy, and Arterial StiffnessR01HL105301 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LEOPOLD, JANE A · 2010 to 2013
$1.6M
PLATELET DERIVED REACTIVE OXYGEN SPECIES AND PLAQUER01HL061795 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LOSCALZO, JOSEPH · 1998 to 2006
$1.6M
Targeted Delivery of Progenitor Cells to the LungP50HL107192 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI CHOI, AUGUSTINE M, LOSCALZO, JOSEPH · 2011 to 2012
$1.0M
Aldosterone impairs endothelin B-dependent synthesis of nitric oxide to promote pK08HL111207 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI MARON, BRADLEY · 2013 to 2017
$754k
Functions of the Hypoxia-Induced MicroRNA-210 in Pulmonary Vascular EndotheliumK08HL096834 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI CHAN, STEPHEN Y · 2010 to 2014
$687k
NHLBI NIH HHS 1K08HL111207-01A1NHLBI NIH HHS 5K08HL096834NHLBI NIH HHS HL070819NHLBI NIH HHS HL105301NHLBI NIH HHS HL107192NHLBI NIH HHS HL108630NHLBI NIH HHS HL48743NHLBI NIH HHS HL61795NHLBI NIH HHS K08 HL096834NHLBI NIH HHS K08 HL111207NHLBI NIH HHS P01 HL048743NHLBI NIH HHS P50 HL107192NHLBI NIH HHS R01 HL061795NHLBI NIH HHS R01 HL105301NHLBI NIH HHS R01 HL139613NHLBI NIH HHS R37 HL061795NHLBI NIH HHS T32 HL007633NHLBI NIH HHS U01 HL108630NHLBI NIH HHS U54 HL070819
6 · The paper itself

Abstract

backgroundThe molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension, suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in pulmonary arterial hypertension. METHODS AND

resultsPatients with pulmonary arterial hypertension, rats with Sugen/hypoxia-pulmonary arterial hypertension, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein-1 site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-small interfering RNA or treated with the activator protein-1 inhibitor SR-11302 [3-methyl-7-(4-methylphenyl)-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid], hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in vivo.

conclusionOur findings identify autonomous aldosterone synthesis in HPAECs attributable to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular remodeling and fibrosis.

Indexed as

AldosteroneAnimalsCells, CulturedEndothelial CellsHumansHypoxiaMaleMiceMice, Inbred C57BLPhosphoproteinsPulmonary ArteryPulmonary FibrosisRandom AllocationRatsRats, Sprague-DawleySteroidogenic Acute Regulatory ProteinAldosteronePhosphoproteinsSteroidogenic Acute Regulatory Proteinaldosteronecell hypoxiafibrosishypertension, pulmonary

Identifiers

PMID25001622
PMCPMC4090713
OpenAlexW2148840917

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.