Evidence map›Paper›PMID 30602302›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2019

Disturbed Flow Increases UBE2C (Ubiquitin E2 Ligase C) via Loss of miR-483-3p, Inducing Aortic Valve Calcification by the pVHL (von Hippel-Lindau Protein) and HIF-1α (Hypoxia-Inducible Factor-1α) Pathway in Endothelial Cells.

Joan Fernandez Esmerats, Nicolas Villa-Roel, Sandeep Kumar, Lina Gu, Md Tausif Salim, Michael Ohh, W Robert Taylor, Robert M Nerem, Ajit P Yoganathan, Hanjoong Jo

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

Article in Arteriosclerosis, thrombosis, and vascular biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.

0numbers the graph read from it
0cells of the map it votes in
51citing papers in PubMed
6.8field-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

51 citing papers in PubMed, 77 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. Review
  9. Article
  10. Article
  11. Review
  12. Article
  13. Review
  14. Review
  15. Article
  16. Review
  17. Review
  18. Myeloid CCN3 protects against aortic valve calcification.Cell communication and signaling : CCS · 2023
    Article
  19. Emerging role of exosomes in vascular diseases.Frontiers in cardiovascular medicine · 2023
    Review
  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

10 authors at 4 institutions in 2 countries.

Joan Fernandez EsmeratsFrom the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.).
Nicolas Villa-RoelFrom the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.).
Sandeep KumarFrom the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.).
Lina GuFrom the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.).
Md Tausif SalimSchool of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta (M.T.S., A.P.Y.).
Michael OhhDepartment of Biochemistry, Faculty of Medicine, University of Toronto, Ontario, Canada (M.O.).
W Robert TaylorFrom the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.).
Robert M NeremParker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta (R.M.N.).
Ajit P YoganathanFrom the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.).
Hanjoong JoFrom the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.).
Georgia Institute of Technology · USThe Wallace H. Coulter Department of Biomedical Engineering · USEmory University · USUniversity of Toronto · CA

Funding

T cell triggering events and hypertensionP01HL095070 · NHLBI · EMORY UNIVERSITY · PI GRIENDLING, KATHY K · 2009 to 2019
$20.5M
Research Training Program Plan on Cell and Tissue Engineering (CTEng)T32GM008433 · NIGMS · GEORGIA INSTITUTE OF TECHNOLOGY · PI GARCIA, ANDRES J · 1991 to 2021
$7.1M
Shear stress, endothelial miRNAs, and AV calcificationR01HL119798 · NHLBI · EMORY UNIVERSITY · PI JO, HANJOONG · 2013 to 2022
$4.7M
Metabolomics of subclinical and clinical cardiovascular diseaseP20HL113451 · NHLBI · EMORY UNIVERSITY · PI JONES, DEAN PAUL · 2012 to 2016
$4.3M
Role of flow-sensitive KLK10 in endothelial dysfunction and atherosclerosisR01HL139757 · NHLBI · EMORY UNIVERSITY · PI JO, HANJOONG · 2018 to 2021
$1.6M
NHLBI NIH HHS P01 HL095070NHLBI NIH HHS P20 HL113451NHLBI NIH HHS R01 HL119798NHLBI NIH HHS R01 HL139757NIGMS NIH HHS T32 GM008433
6 · The paper itself

Abstract

Objective- Calcific aortic valve (AV) disease, characterized by AV sclerosis and calcification, is a major cause of death in the aging population; however, there are no effective medical therapies other than valve replacement. AV calcification preferentially occurs on the fibrosa side, exposed to disturbed flow (d-flow), whereas the ventricularis side exposed to predominantly stable flow remains protected by unclear mechanisms. Here, we tested the role of novel flow-sensitive UBE2C (ubiquitin E2 ligase C) and microRNA-483-3p (miR-483) in flow-dependent AV endothelial function and AV calcification. Approach and Results- Human AV endothelial cells and fresh porcine AV leaflets were exposed to stable flow or d-flow. We found that UBE2C was upregulated by d-flow in human AV endothelial cells in the miR-483-dependent manner. UBE2C mediated OS-induced endothelial inflammation and endothelial-mesenchymal transition by increasing the HIF-1α (hypoxia-inducible factor-1α) level. UBE2C increased HIF-1α by ubiquitinating and degrading its upstream regulator pVHL (von Hippel-Lindau protein). These in vitro findings were corroborated by immunostaining studies using diseased human AV leaflets. In addition, we found that reduction of miR-483 by d-flow led to increased UBE2C expression in human AV endothelial cells. The miR-483 mimic protected against endothelial inflammation and endothelial-mesenchymal transition in human AV endothelial cells and calcification of porcine AV leaflets by downregulating UBE2C. Moreover, treatment with the HIF-1α inhibitor (PX478) significantly reduced porcine AV calcification in static and d-flow conditions. Conclusions- These results suggest that miR-483 and UBE2C and pVHL are novel flow-sensitive anti- and pro-calcific AV disease molecules, respectively, that regulate the HIF-1α pathway in AV. The miR-483 mimic and HIF-1α pathway inhibitors may serve as potential therapeutics of calcific AV disease.

Indexed as

HemorheologyAnimalsAortic ValveAortic Valve StenosisCalcinosisCell AdhesionCells, CulturedCell TransdifferentiationEndothelial CellsFemaleHumansHypoxia-Inducible Factor 1, alpha SubunitInflammationMicroRNAsMonocytesMustard Compounds2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxideHIF1A protein, humanHypoxia-Inducible Factor 1, alpha SubunitMicroRNAsMIRN483 microRNA, humanMustard CompoundsOligonucleotidesPhenylpropionatesRNA, Small InterferingUBE2C protein, humanUbiquitin-Conjugating EnzymesVHL protein, humanVon Hippel-Lindau Tumor Suppressor Proteinaortic valveaortic valve stenosisendothelial cellsendothelial-to-mesenchymal transitioninflammationmicroRNAsubiquitination

Identifiers

PMID30602302
PMCPMC6393167
OpenAlexW2908079993

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.