Evidence map›Paper›PMID 34157861›Full record

ArticleCirculation2021

Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Taijyu Satoh, Longfei Wang, Cristina Espinosa-Diez, Bing Wang, Scott A Hahn, Kentaro Noda, Elizabeth R Rochon, Matthew R Dent, Andrea R Levine, Jeffrey J Baust and 15 more

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

Article in Circulation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.

0numbers the graph read from it
0cells of the map it votes in
53citing papers in PubMed
9.2field-weighted citation impact, top 1% 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

53 citing papers in PubMed, 81 citations in OpenAlex.

  1. Temporal Dissociation of Impaired Glucose Tolerance, Adipose Lipid Remodeling and Endothelial Dysfunction in Aorta After HFD Withdrawal.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026
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  9. Sexual dimorphism in animal models of heart failure with preserved ejection fraction.Journal of applied physiology (Bethesda, Md. : 1985) · 2025
    Review
  10. Article
  11. Regulatory roles of PIWI-interacting RNAs in cardiovascular disease.American journal of physiology. Heart and circulatory physiology · 2025
    Review
  12. Review
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  14. Article
  15. The Impact of Single Nucleotide Polymorphisms and Other Mechanisms on Aspirin Resistance.Cardiovascular & hematological disorders drug targets · 2025
    Review
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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

25 authors at 7 institutions in 2 countries.

Taijyu SatohPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Longfei WangPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Cristina Espinosa-DiezPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Bing WangDepartment of Orthopedic Surgery (B.W.), University of Pittsburgh, PA.
Scott A HahnPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Kentaro NodaDivision of Lung Transplant and Lung Failure, Department of Cardiothoracic Surgery (K.N.), University of Pittsburgh, PA.
Elizabeth R RochonPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Matthew R Dent
Andrea R LevinePulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore (A.L.).
Jeffrey J BaustPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Samuel WymanRangos Research Center Animal Imaging Core and Developmental Biology (S.W., Y.L.W.), University of Pittsburgh, PA.
Yijen L WuRangos Research Center Animal Imaging Core and Developmental Biology (S.W., Y.L.W.), University of Pittsburgh, PA.
Georgios A TriantafyllouDivision of Pulmonary, Allergy and Critical Care Medicine (G.A.T., M.T.G.), University of Pittsburgh School of Medicine, PA.
Ying TangPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Mike ReynoldsPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Sruti ShivaPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Cynthia St HilairePittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Delphine GomezPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Dmitry A GoncharovPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Elena A GoncharovaPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Stephen Y ChanPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Adam C StraubPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Yen-Chun LaiDivision of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis (Y.-C.L.).
Charles F McTiernanPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
Mark T GladwinPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.S., L.W., C.E.-D., S.A.H., E.R.R., M.R.D., J.J.B., Y.T., M.R., S.S., C.S.H., D.G., D.A.G., E.A.G., S.Y.C., A.C.S., C.F.M., M.T.G.), University of Pittsburgh School of Medicine, PA.
University of Pittsburgh · USDentsply Sirona (United States) · USIndiana University – Purdue University Indianapolis · USLung Institute · USPulmonary and Allergy Associates · USUnited States Nuclear Regulatory Commission · USUniversity of Maryland, Baltimore · US

Funding

Vascular Subphenotypes of Lung DiseaseP01HL103455 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MORA, ANA LUCIA · 2011 to 2020
$26.1M
Defining the Complex Biology of the miR-130/301 Family in Pulmonary HypertensionR01HL124021 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y · 2014 to 2025
$4.9M
Role of Skeletal Muscle in Pulmonary Vascular RemodelingR01HL142638 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI Yen Chun Charly Lai · 2018 to 2026
$4.9M
Training Program in Imaging Sciences in Translational Cardiovascular ResearchT32HL129964 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Flordeliza S Villanueva · 2016 to 2026
$4.7M
Iron-Sulfur Deficiency as a Critical Pathogenic Cause of Pulmonary HypertensionR01HL122596 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y · 2015 to 2024
$4.5M
HIPPO Signaling in Pulmonary Arterial HypertensionR01HL130261 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GONCHAROVA, ELENA · 2016 to 2023
$3.5M
Epigenetic control of smooth muscle cell phenotype during microvascular remodelingR01HL146465 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Delphine Gomez · 2019 to 2026
$3.4M
TSC2 Signaling in Pulmonary Arterial HypertensionR01HL113178 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GONCHAROVA, ELENA · 2012 to 2021
$3.1M
GATA-6 in pulmonary arterial hypertensionR01HL150638 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · PI GONCHAROVA, ELENA, TROJANOWSKA, MARIA · 2020 to 2023
$2.6M
Molecular Drivers of Vascular Stiffness and Metabolic Dysfunction in HIV-Induced Pulmonary Arterial HypertensionR01HL138437 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAN, STEPHEN Y, NORRIS, KAREN A · 2017 to 2020
$2.4M
Novel role of smooth muscle B5 reductase in Sickle Cell DiseaseR01HL133864 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI STRAUB, ADAM CARL · 2016 to 2019
$2.4M
Vascular Smooth Muscle and Blood Pressure Regulation By Cyb5R3²R01HL128304 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI STRAUB, ADAM CARL · 2016 to 2020
$2.4M
NCATS NIH HHS UH2 TR002073NCATS NIH HHS UH3 TR002073NHLBI NIH HHS K22 HL117917NHLBI NIH HHS P01 HL103455NHLBI NIH HHS R01 HL113178NHLBI NIH HHS R01 HL122596NHLBI NIH HHS R01 HL124021NHLBI NIH HHS R01 HL128304NHLBI NIH HHS R01 HL130261NHLBI NIH HHS R01 HL133003NHLBI NIH HHS R01 HL133864NHLBI NIH HHS R01 HL138437NHLBI NIH HHS R01 HL142638NHLBI NIH HHS R01 HL142932NHLBI NIH HHS R01 HL146465NHLBI NIH HHS R01 HL150638NHLBI NIH HHS T32 HL129964NIBIB NIH HHS R21 EB023507NIH HHS S10 OD023684
6 · The paper itself

Abstract

backgroundMany patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells.

methodsWe used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress.

resultsObese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH.

conclusionsIn heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.

Indexed as

AnimalsAnimals, Genetically ModifiedBiomarkersCCAAT-Binding FactorDisease Models, AnimalDisease SusceptibilityExerciseGene Expression RegulationHeart FailureHumansHypertension, PulmonaryMetabolic SyndromeMicroRNAsMitochondria, HeartMyocytes, Smooth MusclePhenotypeBiomarkersCCAAT-Binding FactorMicroRNAsMIRN193 microRNA, humanNFYA protein, humanReactive Oxygen SpeciesSoluble Guanylyl CyclaseMIRN193 microRNA, humannitric oxidenuclear factor Ypulmonary hypertension

Identifiers

PMID34157861
PMCPMC8384699
OpenAlexW3174056182

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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.