Evidence map›Paper›PMID 26438688›Full record

ArticleCirculation research2015

FoxO4 promotes early inflammatory response upon myocardial infarction via endothelial Arg1.

Min Zhu, Sean C Goetsch, Zhaoning Wang, Robert Luo, Joseph A Hill, Jay Schneider, Sidney M Morris, Zhi-Ping Liu

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

Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.

0numbers the graph read from it
0cells of the map it votes in
56citing papers in PubMed
3.6field-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

56 citing papers in PubMed, 77 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
  9. Article
  10. Review
  11. Review
  12. Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Review
  13. Review
  14. Article
  15. Article
  16. The Role of ncRNAs in Cardiac Infarction and Regeneration.Journal of cardiovascular development and disease · 2023
    Review
  17. Article
  18. FOXOs: masters of the equilibrium.The FEBS journal · 2022
    Review
  19. Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022
    Article
  20. Article
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.

Min ZhuFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Sean C GoetschFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Zhaoning WangFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Robert LuoFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Joseph A HillFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Jay SchneiderFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Sidney M MorrisFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.).
Zhi-Ping LiuFrom the Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (M.Z., S.C.G., Z.W., R.L., J.A.H., J.S., Z.-P.L.); and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA (S.M.M.). zhi-ping.Liu@utsouthwestern.edu.
University of Pittsburgh · US

Funding

Microenvironmental control of progenitors in organ dysfunction and repairU01HL100401 · NHLBI · UT SOUTHWESTERN MEDICAL CENTER · PI OLSON, ERIC N, SCHNEIDER, JAY W · 2009 to 2015
$8.3M
Role of Arginase in Inflammation and TraumaR01GM057384 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MORRIS, SIDNEY MACHEN · 1998 to 2012
$3.8M
Role of FOXO4 in atherosclerosisR01HL085749 · NHLBI · UT SOUTHWESTERN MEDICAL CENTER · PI LIU, ZHI-PING · 2006 to 2010
$1.9M
STIM1: Master Regulator of Calcium Homeostasis in CardiomyocytesR01HL120732 · NHLBI · UT SOUTHWESTERN MEDICAL CENTER · PI HILL, JOSEPH A · 2013 to 2016
$1.6M
Epigenetic Regulation of Cardiac Hypertrophy and Heart FailureR01HL109471 · NHLBI · UT SOUTHWESTERN MEDICAL CENTER · PI LIU, ZHI-PING · 2012 to 2015
$1.6M
NHLBI NIH HHS HL-100401NHLBI NIH HHS HL109471NHLBI NIH HHS HL-120732NHLBI NIH HHS R01 HL085749NHLBI NIH HHS R01 HL109471NHLBI NIH HHS UO1-5U01HL10040106NIGMS NIH HHS R01 GM057384
6 · The paper itself

Abstract

rationaleInflammation in post-myocardial infarction (MI) is necessary for myocyte repair and wound healing. Unfortunately, it is also a key component of subsequent heart failure pathology. Transcription factor forkhead box O4 (FoxO4) regulates a variety of biological processes, including inflammation. However, its role in MI remains unknown.

objectiveTo test the hypothesis that FoxO4 promotes early post-MI inflammation via endothelial arginase 1 (Arg1). METHODS AND

resultsWe induced MI in wild-type and FoxO4(-/-) mice. FoxO4(-/-) mice had a significantly higher post-MI survival, better cardiac function, and reduced infarct size. FoxO4(-/-) hearts had significantly fewer neutrophils, reduced expression of cytokines, and competitive nitric oxide synthase inhibitor Arg1. We generated conditional FoxO4 knockout mice with FoxO4 deleted in cardiac mycoytes or endothelial cells. FoxO4 endothelial cell-specific knockout mice showed significant post-MI improvement of cardiac function and reduction of neutrophil accumulation and cytokine expression, whereas FoxO4 cardiac mycoyte-specific knockout mice had no significant difference in cardiac function and post-MI inflammation from those of control littermates. FoxO4 binds the Foxo-binding site in the Arg1 promoter and activates Arg1 transcription. FoxO4 knockdown in human aortic endothelial cells upregulated nitric oxide on ischemia and suppressed monocyte adhesion that can be reversed by ectopic-expression of Arg1. Furthermore, chemical inhibition of Arg1 in wild-type mice had similar cardioprotection and reduced inflammation after MI as FoxO4 inactivation and administration of nitric oxide synthase inhibitor to FoxO4 KO mice reversed the beneficial effects of FoxO4 deletion on post-MI cardiac function.

conclusionsFoxO4 activates Arg1 transcription in endothelial cells in response to MI, leading to downregulation of nitric oxide and upregulation of neutrophil infiltration to the infarct area.

Indexed as

AnimalsAnti-Inflammatory AgentsArginaseBinding SitesCell AdhesionCell Cycle ProteinsCoculture TechniquesDisease Models, AnimalEndothelial CellsEnzyme InductionForkhead Transcription FactorsHEK293 CellsHumansInflammationMaleMice, Inbred C57BLAnti-Inflammatory AgentsARG1 protein, humanArg1 protein, mouseArginaseCell Cycle ProteinsForkhead Transcription FactorsFOXO4 protein, humanFoxO4 protein, mouseNitric OxideTranscription Factorsarginaseendothelial cellsFoxO4 protein, mouseinflammationmyocardial infarction

Identifiers

PMID26438688
PMCPMC4710860
OpenAlexW2118189941

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

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.