Evidence map›Paper›PMID 28588076›Full record

ArticleCirculation2017

Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-β and Cardiac Fibrosis.

Panagiotis Flevaris, Sadiya S Khan, Mesut Eren, Adam J T Schuldt, Sanjiv J Shah, Daniel C Lee, Sweta Gupta, Amy D Shapiro, Paul W Burridge, Asish K Ghosh and 1 more

Registry-linked trialOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05317806 (Use of Metformin in Prevention and Treatment of Cardiac Fibrosis in PAI-1 Deficient Population), which is not on this map. Cited by 48 papers.

0numbers the graph read from it
0cells of the map it votes in
48citing papers in PubMed
2.5field-weighted citation impact, top 11% 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.

NCT05317806 phase4active not recruitingnot on this mapstarted 2022, after this paper: background citation

Use of Metformin in Prevention and Treatment of Cardiac Fibrosis in PAI-1 Deficient Population

TypeinterventionalSponsorIndiana Hemophilia &Thrombosis Center, Inc.Ran2022 to 2027Enrolled15ConditionsPlasminogen Activator Inhibitor-1 Deficiency, Cardiac FibrosisArmsMetformin Extended Release Oral Tablet
3 · Its place in the literature

Who cites it

48 citing papers in PubMed, 91 citations in OpenAlex.

  1. Review
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  3. Article
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  7. Review
  8. Article
  9. Review
  10. Reversing PAI-1 deficiency in blood using mRNA lipid nanoparticles.Molecular therapy. Methods & clinical development · 2025
    Article
  11. Plasminogen Activator Inhibitor 1 Controls Abdominal Aortic Aneurism Formation via the Modulation of TGF-β/Smad2/3 Signaling in Mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025
    Article
  12. Article
  13. Article
  14. Review
  15. A comprehensive study on the impact ofFrontiers in cardiovascular medicine · 2025
    Article
  16. Observational
  17. Article
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  20. Review
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

11 authors at 1 institution in 2 countries.

Panagiotis FlevarisFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Sadiya S KhanFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Mesut ErenFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Adam J T SchuldtFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Sanjiv J ShahFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Daniel C LeeFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Sweta GuptaFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Amy D ShapiroFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Paul W BurridgeFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Asish K GhoshFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.).
Douglas E VaughanFrom Division of Cardiology, Department of Medicine (P.F., S.S.K., M.E., A.J.T.S., S.J.S., D.C.L., A.K.G., D.E.V.); Feinberg Cardiovascular Research Institute (P.F., S.S.K., S.J.S., D.C.L., A.K.G., D.E.V.), Department of Pharmacology (A.J.T.S., P.W.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Indiana Hemophilia and Thrombosis Center, Indianapolis (S.G., A.D.S.). d-vaughan@northwestern.edu.
Norwegian Womens Public Health Association · NO

Funding

Pleiotropic Role of PAI-1 in Cardiovascular AgingR01HL051387 · NHLBI · VANDERBILT UNIVERSITY · PI VAUGHAN, DOUGLAS E · 1994 to 2023
$7.9M
The Role of Plasminogen Activator Inhibitor-1 in the Development and Progression of ObesityF32HL129695 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI KHAN, SADIYA SANA · 2015 to 2016
$134k
Cardiomyocyte Integrin-Matrix Interactions Regulate Cardiac FibrosisF32HL131301 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI FLEVARIS, PANAGIOTIS · 2016 to 2017
$127k
NHLBI NIH HHS F32 HL129695NHLBI NIH HHS F32 HL131301NHLBI NIH HHS R01 HL051387
6 · The paper itself

Abstract

backgroundFibrosis is the pathological consequence of stress-induced tissue remodeling and matrix accumulation. Increased levels of plasminogen activator inhibitor type I (PAI-1) have been shown to promote fibrosis in multiple organ systems. Paradoxically, homozygous genetic deficiency of PAI-1 is associated with spontaneous age-dependent, cardiac-selective fibrosis in mice. We have identified a novel PAI-1-dependent mechanism that regulates cardiomyocyte-derived fibrogenic signals and cardiac transcriptional pathways during injury.

methodsCardiac fibrosis in subjects with homozygous mutation in

resultsCardiac fibrosis was detected in 2 otherwise healthy humans with complete PAI-1 deficiency because of a homozygous frameshift mutation in

conclusionsPAI-1 is an essential repressor of cardiac fibrosis in mammals. We define a novel cardiomyocyte-specific regulatory mechanism for TGF-β production by PAI-1, which explains the paradoxical effect of PAI-1 deficiency in promoting cardiac-selective fibrosis. Thus, PAI-1 is a molecular switch that controls the cardiac TGF-β axis and its early transcriptional effects that lead to myocardial fibrosis.

Indexed as

Angiotensin IIAnimalsBone Morphogenetic Protein 7CardiomegalyCells, CulturedFemaleFrameshift MutationHumansMagnetic Resonance Imaging, CineMaleMiceMice, Inbred C57BLMice, KnockoutMyocytes, CardiacPlasminogen Activator Inhibitor 1RNAAngiotensin IIBone Morphogenetic Protein 7Plasminogen Activator Inhibitor 1RNASERPINE1 protein, humanSmad6 ProteinTransforming Growth Factor betacardiac remodelingcardiomyopathyprotease inhibitor

Identifiers

PMID28588076
PMCPMC5784400
OpenAlexW2621415901

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

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.