Evidence map›Paper›PMID 42626780›Full record

ArticleCirculation research2026

Desmoplakin Loss Leads to PKC- and Src-Mediated Contractile Dysfunction in Cardiomyocytes.

Ilhan Gokhan, Margaret McKay, Xia Li, Michele Zanetti, Jonathan M Granger, Jack M Sendek, Alex J Mora Pagan, Kenneth S Campbell, Fadi G Akar, Stuart G Campbell

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In one paragraph

Article in Circulation research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

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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

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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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors.

Ilhan GokhanDepartment of Biomedical Engineering (I.G., M.M., X.L., M.Z., J.M.S., F.G.A., S.G.C.), Yale University, New Haven, CT.ORCID 0000-0003-3014-6070
Margaret McKayDepartment of Biomedical Engineering (I.G., M.M., X.L., M.Z., J.M.S., F.G.A., S.G.C.), Yale University, New Haven, CT.ORCID 0000-0003-2968-420X
Xia LiDepartment of Biomedical Engineering (I.G., M.M., X.L., M.Z., J.M.S., F.G.A., S.G.C.), Yale University, New Haven, CT.ORCID 0009-0008-2841-6960
Michele ZanettiDepartment of Biomedical Engineering (I.G., M.M., X.L., M.Z., J.M.S., F.G.A., S.G.C.), Yale University, New Haven, CT.
Jonathan M GrangerDivision of Cardiology, Department of Internal Medicine (J.M.G., F.G.A.), Yale University, New Haven, CT.ORCID 0000-0002-0848-9547
Jack M SendekDepartment of Biomedical Engineering (I.G., M.M., X.L., M.Z., J.M.S., F.G.A., S.G.C.), Yale University, New Haven, CT.ORCID 0009-0002-2731-3296
Alex J Mora PaganDepartment of Cellular and Molecular Physiology (A.J.M.P., S.G.C.), Yale University, New Haven, CT.ORCID 0000-0002-0859-5657
Kenneth S CampbellDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Kentucky, Lexington (K.S.C.).ORCID 0000-0001-5615-5958
Fadi G AkarDepartment of Biomedical Engineering (I.G., M.M., X.L., M.Z., J.M.S., F.G.A., S.G.C.), Yale University, New Haven, CT.ORCID 0000-0001-9146-8407
Stuart G CampbellDepartment of Biomedical Engineering (I.G., M.M., X.L., M.Z., J.M.S., F.G.A., S.G.C.), Yale University, New Haven, CT.ORCID 0000-0002-1527-0770

Funding

Desmoplakinopathies: Integrated Pathophysiology and TherapeuticsR01HL163092 · NHLBI · YALE UNIVERSITY · PI FADI GABRIEL AKAR, STUART G CAMPBELL · 2023 to 2026
$2.7M
Elucidating the Role of Biomechanical Strain in Atrial Physiology and ArrhythmiasF30HL170584 · NHLBI · YALE UNIVERSITY · PI Ilhan Gokhan · 2023 to 2026
$176k
NHLBI NIH HHS F30 HL170584NHLBI NIH HHS R01 HL163092
6 · The paper itself

Abstract

backgroundMutations in

methodsWe use 3 complementary models to characterize desmoplakin-linked cardiomyopathy: induced pluripotent stem cell-derived engineered heart tissue expressing R451G desmoplakin, a heterozygous

resultsUsing induced pluripotent stem cell-derived engineered heart tissue and isolated mouse ventricular cardiomyocytes, we recapitulate a disease phenotype consistent with desmoplakin cardiomyopathy and identify shortened resting sarcomere length as a pathogenic mechanism for contractile dysfunction. Phosphorylation of Src and protein kinase C underlies sarcomere shortening in mutant tissues, and pharmacological inhibition of these kinases rescues sarcomere length. Notably, these sarcomeric and biochemical hallmarks are also present in human hearts bearing different desmoplakin mutations. We next identify the redistribution of mechanical force at cardiomyocyte junctions as a proximal factor that may promote mechanoactivation of proto-oncogene tyrosine-protein kinase Src. Finally, we rescue sarcomere length and contractile function in

conclusionsOur study reveals a mechanism by which a desmosomal mutation affects cardiomyocyte function at the sarcomere level through activation of key signaling pathways that have not previously been implicated in desmoplakin cardiomyopathy.

Indexed as

CardiomyopathiesDesmoplakinsMyocardial ContractionMyocytes, CardiacProtein Kinase Csrc-Family KinasesAnimalsCells, CulturedHumansInduced Pluripotent Stem CellsMiceMice, TransgenicMutation, MissenseProto-Oncogene MasSarcomeresDesmoplakinsDSP protein, humanDsp protein, mouseMAS1 protein, humanProtein Kinase CProto-Oncogene Massrc-Family Kinasescardiomyopathiesdesmoplakinprotein kinase Cprotein-tyrosine kinasessarcomeres

Identifiers

PMID42626780
PMCPMC13501905

What OpenQuestion holds

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Registered trials

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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.