Evidence map›Paper›PMID 25336633›Full record

ArticleCirculation2015

Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension.

Jongmin Kim, Cheol Hwangbo, Xiaoyue Hu, Yujung Kang, Irinna Papangeli, Devi Mehrotra, Hyekyung Park, Hyekyung Ju, Danielle L McLean, Suzy A Comhair and 2 more

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

Article in Circulation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.

0numbers the graph read from it
0cells of the map it votes in
76citing papers in PubMed
7.0field-weighted citation impact, top 3% 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

76 citing papers in PubMed, 123 citations in OpenAlex.

  1. The histone deacetylase family in health and disease.Signal transduction and targeted therapy · 2026
    Review
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  6. Sildenafil Effect on Atrial Natriuretic Peptide Level in Pulmonary Hypertensive Rats.Cardiovascular & hematological agents in medicinal chemistry · 2025
    Article
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  15. Article
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  18. Article
  19. Molecular Pathways in Pulmonary Arterial Hypertension.International journal of molecular sciences · 2022
    Review
  20. Review

16 more citing papers are in PubMed but not listed here.

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

12 authors at 1 institution in 1 country.

Jongmin KimFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Cheol HwangboFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Xiaoyue HuFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Yujung KangFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Irinna PapangeliFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Devi MehrotraFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Hyekyung ParkFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Hyekyung JuFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Danielle L McLeanFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Suzy A ComhairFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Serpil C ErzurumFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.).
Hyung J ChunFrom the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT (J.K., C.H., X.H., Y.K., I.P., D.M., H.P., H.J., D.L.M., H.J.C.); the Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and the Department of Pathobiology, The Lerner Institute, The Cleveland Clinic Foundation, Cleveland, OH (S.A.C., S.C.E.). hyung.chun@yale.edu.
Sookmyung Women's University · KR

Funding

Pulmonary Hypertension Breakthrough InitiativeR24HL123767 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI ALDRED, MICHEALA A, ERZURUM, SERPIL C. · 2014 to 2017
$10.1M
NITRIC OXIDE PRODUCTION AND REACTIONS IN THE LUNGR01HL060917 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI Serpil C. Erzurum · 1999 to 2026
$6.3M
Airway redox biochemistry as a deteriminant of asthma phenotype during adolescen*U10HL109250 · NHLBI · UNIVERSITY OF VIRGINIA · PI ERZURUM, SERPIL C., GASTON, BENJAMIN · 2011 to 2016
$4.2M
Nitric Oxide in Pulmonary HypertensionR37HL060917 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI ERZURUM, SERPIL C. · 2009 to 2018
$3.9M
Pulmonary Vascular-Right Ventricular Axis Research ProgramR01HL115008 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI ERZURUM, SERPIL C., PRASAD, SATHYAMANGLA V · 2012 to 2016
$3.1M
Role of MicroRNAs 424 and 503 in Pulmonary Arterial HypertensionR01HL113005 · NHLBI · YALE UNIVERSITY · PI CHUN, HYUNG JOON · 2012 to 2016
$2.0M
Role of Apelin in the Systemic and Pulmonary VasculatureK08HL095654 · NHLBI · YALE UNIVERSITY · PI CHUN, HYUNG JOON · 2009 to 2013
$668k
Howard Hughes Medical InstituteNHLBI NIH HHS HL095654NHLBI NIH HHS HL113005NHLBI NIH HHS HL115008NHLBI NIH HHS HL60917NHLBI NIH HHS K08 HL095654NHLBI NIH HHS R01 HL060917NHLBI NIH HHS R01 HL113005NHLBI NIH HHS R01 HL115008NHLBI NIH HHS R24 HL123767NHLBI NIH HHS R37 HL060917NHLBI NIH HHS U10 HL109250
6 · The paper itself

Abstract

backgroundPulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary arterioles, characterized by increased pulmonary arterial pressure and right ventricular failure. The cause of PAH is complex, but aberrant proliferation of the pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells is thought to play an important role in its pathogenesis. Understanding the mechanisms of transcriptional gene regulation involved in pulmonary vascular homeostasis can provide key insights into potential therapeutic strategies. METHODS AND

resultsWe demonstrate that the activity of the transcription factor myocyte enhancer factor 2 (MEF2) is significantly impaired in the PAECs derived from subjects with PAH. We identified MEF2 as the key cis-acting factor that regulates expression of a number of transcriptional targets involved in pulmonary vascular homeostasis, including microRNAs 424 and 503, connexins 37, and 40, and Krűppel Like Factors 2 and 4, which were found to be significantly decreased in PAH PAECs. The impaired MEF2 activity in PAH PAECs was mediated by excess nuclear accumulation of 2 class IIa histone deacetylases (HDACs) that inhibit its function, namely HDAC4 and HDAC5. Selective, pharmacological inhibition of class IIa HDACs led to restoration of MEF2 activity in PAECs, as demonstrated by increased expression of its transcriptional targets, decreased cell migration and proliferation, and rescue of experimental pulmonary hypertension models.

conclusionsOur results demonstrate that strategies to augment MEF2 activity hold potential therapeutic value in PAH. Moreover, we identify selective HDAC IIa inhibition as a viable alternative approach to avoid the potential adverse effects of broad spectrum HDAC inhibition in PAH.

Indexed as

AnimalsApelinArteriolesCells, CulturedDisease Models, AnimalDrug Evaluation, PreclinicalEndothelial CellsFibroblast Growth Factor 2HemodynamicsHistone Deacetylase InhibitorsHydroxamic AcidsHypertension, PulmonaryHypertrophy, Right VentricularHypoxiaIntercellular Signaling Peptides and ProteinsMaleApelinAPLN protein, humanFibroblast Growth Factor 2Histone Deacetylase InhibitorsHydroxamic AcidsIntercellular Signaling Peptides and ProteinsMC1568MEF2 Transcription FactorsMicroRNAsMonocrotalinePyrrolesRNA, Small Interferingendothelial cellspulmonary hypertensiontranscriptional activation

Identifiers

PMID25336633
PMCPMC4293354
OpenAlexW2032033480

What OpenQuestion holds

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Registered trials

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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.