Evidence map›Paper›PMID 29472234›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2018

Hypoxia Triggers SENP1 (Sentrin-Specific Protease 1) Modulation of KLF15 (Kruppel-Like Factor 15) and Transcriptional Regulation of Arg2 (Arginase 2) in Pulmonary Endothelium.

Deepesh Pandey, Yohei Nomura, Max C Rossberg, Daijiro Hori, Anil Bhatta, Gizem Keceli, Thorsten Leucker, Lakshmi Santhanam, Larissa A Shimoda, Dan Berkowitz and 1 more

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

Article in Arteriosclerosis, thrombosis, and vascular biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
1.4field-weighted citation impact, top 19% 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

18 citing papers in PubMed, 29 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Article
  5. The emerging roles of SUMOylation in pulmonary diseases.Molecular medicine (Cambridge, Mass.) · 2023
    Review
  6. Article
  7. Article
  8. Review
  9. Review
  10. Article
  11. Article
  12. Vascular Endothelial Cells and Innate Immunity.Arteriosclerosis, thrombosis, and vascular biology · 2020
    Review
  13. Annual Report on Sex in Preclinical Studies:Arteriosclerosis, thrombosis, and vascular biology · 2020
    Review
  14. Article
  15. Article
  16. Review
  17. Review
  18. Observational
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.

Deepesh PandeyFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD. Dpandey2@jhmi.edu.
Yohei NomuraFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Max C RossbergFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Daijiro HoriFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Anil BhattaFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Gizem KeceliFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Thorsten LeuckerFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Lakshmi SanthanamFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Larissa A ShimodaFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Dan BerkowitzFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Lewis RomerFrom the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.
Johns Hopkins University · US

Funding

Institute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1M
Non-Visual Opsins & Vasoregulation: Implications for Vascular TherapyR01HL124213 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI BERKOWITZ, DAN E · 2015 to 2018
$1.6M
American Heart Association-American Stroke Association 13POST16810011NCATS NIH HHS UL1 TR001079NHLBI NIH HHS R01 HL124213
6 · The paper itself

Abstract

objectiveKLF15 (Kruppel-like factor 15) has recently been shown to suppress activation of proinflammatory processes that contribute to atherogenesis in vascular smooth muscle, however, the role of KLF15 in vascular endothelial function is unknown. Arginase mediates inflammatory vasculopathy and vascular injury in pulmonary hypertension. Here, we tested the hypothesis that KLF15 is a critical regulator of hypoxia-induced Arg2 (arginase 2) transcription in human pulmonary microvascular endothelial cells (HPMEC). APPROACH AND

resultsQuiescent HPMEC express ample amounts of full-length KLF15. HPMECs exposed to 24 hours of hypoxia exhibited a marked decrease in KLF15 protein levels and a reciprocal increase in Arg2 protein and mRNA. Chromatin immunoprecipitation indicated direct binding of KLF15 to the Arg2 promoter, which was relieved with HPMEC exposure to hypoxia. Furthermore, overexpression of KLF15 in HPMEC reversed hypoxia-induced augmentation of Arg2 abundance and arginase activity and rescued nitric oxide (NO) production. Ectopic KLF15 also reversed hypoxia-induced endothelium-mediated vasodilatation in isolated rat pulmonary artery rings. Mechanisms by which hypoxia regulates KLF15 abundance, stability, and compartmentalization to the nucleus in HPMEC were then investigated. Hypoxia triggered deSUMOylation of KLF15 by SENP1 (sentrin-specific protease 1), and translocation of KLF15 from nucleus to cytoplasm.

conclusionsKLF15 is a critical regulator of pulmonary endothelial homeostasis via repression of endothelial Arg2 expression. KLF15 abundance and nuclear compartmentalization are regulated by SUMOylation/deSUMOylation-a hypoxia-sensitive process that is controlled by SENP1. Strategies including overexpression of KLF15 or inhibition of SENP1 may represent novel therapeutic targets for pulmonary hypertension.

Indexed as

Transcription, GeneticActive Transport, Cell NucleusAnimalsArginaseCell HypoxiaCells, CulturedCysteine EndopeptidasesEndothelial CellsGene Expression Regulation, EnzymologicHumansKruppel-Like Transcription FactorsLungMicrovesselsNitric OxideNitric Oxide Synthase Type IIINuclear ProteinsARG2 protein, humanArginaseCysteine EndopeptidasesKLF15 protein, humanKruppel-Like Transcription FactorsNitric OxideNitric Oxide Synthase Type IIINOS3 protein, humanNuclear ProteinsProteasome Endopeptidase ComplexSENP1 protein, humanarginasecytoplasmendotheliumhypoxiapulmonary artery

Identifiers

PMID29472234
PMCPMC6738933
OpenAlexW2788306468

What Socratic 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 Socratic graph.