Evidence map›Paper›PMID 25253076›Full record

ArticleCardiovascular research2014

Arrhythmogenic right ventricular cardiomyopathy mutations alter shear response without changes in cell-cell adhesion.

Venkatesh Hariharan, Angeliki Asimaki, Jarett E Michaelson, Eva Plovie, Calum A MacRae, Jeffrey E Saffitz, Hayden Huang

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

Article in Cardiovascular research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed, 1 pooled it
4.7field-weighted citation impact, top 4% 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

26 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.

  1. Pooled it
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  11. Arrhythmogenic Cardiomyopathy: Molecular Insights for Improved Therapeutic Design.Journal of cardiovascular development and disease · 2020
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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

7 authors at 3 institutions in 1 country.

Venkatesh HariharanDepartment of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 500 W 120th Street, MC 8904, New York, NY 10027, USA.
Angeliki AsimakiDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA Department of Pathology, Harvard Medical School, Boston, MA, USA.
Jarett E MichaelsonDepartment of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 500 W 120th Street, MC 8904, New York, NY 10027, USA.
Eva PlovieDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA Department of Medicine, Harvard Medical School, Boston, MA, USA.
Calum A MacRaeDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA Department of Medicine, Harvard Medical School, Boston, MA, USA.
Jeffrey E SaffitzDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA Department of Pathology, Harvard Medical School, Boston, MA, USA.
Hayden HuangDepartment of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 500 W 120th Street, MC 8904, New York, NY 10027, USA hayden.huang@columbia.edu.
Columbia University · USHarvard University · USBrigham and Women's Hospital · US

Funding

Genetics, Mechanisms and Clinical Phenotypes of Arrhythmogenic CardiomyopathyR01HL116906 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI MARCUS, FRANK I, MESTRONI, LUISA · 2013 to 2016
$9.2M
Disease Mechanisms in ARVCR01HL102361 · NHLBI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI SAFFITZ, JEFFREY E · 2010 to 2013
$1.7M
Columbia AFM System Equipment GrantS10RR027943 · NCRR · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI HUNG, CLARK T. · 2010 to 2010
$496k
NCRR NIH HHS S10RR027943-01NHLBI NIH HHS R01HL102361NHLBI NIH HHS R01 HL116906
6 · The paper itself

Abstract

aimsThe majority of patients diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) have mutations in genes encoding desmosomal proteins, raising the possibility that abnormal intercellular adhesion plays an important role in disease pathogenesis. We characterize cell mechanical properties and molecular responses to oscillatory shear stress in cardiac myocytes expressing mutant forms of the desmosomal proteins, plakoglobin and plakophilin, which are linked to ARVC in patients. METHODS AND

resultsCells expressing mutant plakoglobin or plakophilin showed no differences in cell-cell adhesion relative to controls, while knocking down these proteins weakened cell-cell adhesion. However, cells expressing mutant plakoglobin failed to increase the amount of immunoreactive signal for plakoglobin or N-cadherin at cell-cell junctions in response to shear stress, as seen in control cells. Cells expressing mutant plakophilin exhibited a similar attenuation in the shear-induced increase in junctional plakoglobin immunoreactive signal in response to shear stress, suggesting that the phenotype is independent of the type of mutant protein being expressed. Cells expressing mutant plakoglobin also showed greater myocyte apoptosis compared with controls. Apoptosis rates increased greatly in response to shear stress in cells expressing mutant plakoglobin, but not in controls. Abnormal responses to shear stress in cells expressing either mutant plakoglobin or plakophilin could be reversed by SB216763, a GSK3β inhibitor.

conclusionsDesmosomal mutations linked to ARVC do not significantly affect cell mechanical properties, but cause myocytes to respond abnormally to mechanical stress through a mechanism involving GSK3β. These results may help explain why patients with ARVC experience disease exacerbations following strenuous exercise.

Indexed as

Cell AdhesionMechanotransduction, CellularMutationAnimalsAnimals, NewbornApoptosisArrhythmogenic Right Ventricular DysplasiaCadherinsCells, Culturedgamma CateninGenetic Predisposition to DiseaseGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaIntercellular JunctionsMyocytes, CardiacNerve Tissue ProteinsCadherinsgamma CateninGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaGsk3b protein, ratN-cadherin, ratNerve Tissue ProteinsPlakophilinsProtein Kinase InhibitorsArrhythmiaCardiomyopathyDesmosomePlakoglobinShear stress

Identifiers

PMID25253076
PMCPMC4296114
OpenAlexW1978545794

What OpenQuestion holds

Textmetadata
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.