Evidence map›Paper›PMID 33928785›Full record

ArticleCirculation2021

Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy.

Dries A M Feyen, Isaac Perea-Gil, Renee G C Maas, Magdalena Harakalova, Alexandra A Gavidia, Jennifer Arthur Ataam, Ting-Hsuan Wu, Aryan Vink, Jiayi Pei, Nirmal Vadgama and 12 more

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Article in Circulation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.

0numbers the graph read from it
0cells of the map it votes in
54citing papers in PubMed
5.2field-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

54 citing papers in PubMed, 71 citations in OpenAlex.

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  13. Identification of disease-specific pathways and modifiers in phospholamban R14del cardiomyopathy: rationale, design and baseline characteristics of DECIPHER-PLN cohort.Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation · 2025
    Article
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  20. Genetic landscape of phospholamban cardiomyopathies.Frontiers in cell and developmental biology · 2025
    Review
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

22 authors at 5 institutions in 3 countries.

Dries A M Feyen *Cardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Isaac Perea-Gil *Cardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Renee G C MaasDepartment of Cardiology, Division Heart and Lungs (R.G.C.M., M.H., J.P., J.P.G.S., F.W.A.), University Medical Center Utrecht, University of Utrecht, The Netherlands.
Magdalena HarakalovaDepartment of Cardiology, Division Heart and Lungs (R.G.C.M., M.H., J.P., J.P.G.S., F.W.A.), University Medical Center Utrecht, University of Utrecht, The Netherlands.
Alexandra A GavidiaCardiothoracic Surgery (I.P.-G., A.A.G., J.A.A., T.-H.W., N.V., M.P., Y.Z., L.D., I.K.), Stanford University School of Medicine, Stanford University, CA.
Jennifer Arthur AtaamCardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Ting-Hsuan WuCardiothoracic Surgery (I.P.-G., A.A.G., J.A.A., T.-H.W., N.V., M.P., Y.Z., L.D., I.K.), Stanford University School of Medicine, Stanford University, CA.
Aryan VinkDepartment of Pathology (A.V.), University Medical Center Utrecht, University of Utrecht, The Netherlands.
Jiayi PeiDepartment of Cardiology, Division Heart and Lungs (R.G.C.M., M.H., J.P., J.P.G.S., F.W.A.), University Medical Center Utrecht, University of Utrecht, The Netherlands.
Nirmal VadgamaCardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Albert J SuurmeijerDepartment of Pathology, University Medical Center Groningen, University of Groningen, The Netherlands (A.J.S.).
Wouter P Te RijdtNetherlands Heart Institute, Utrecht (W.P.t.R.).
Michelle VuCardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Prashila L AmatyaCardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Maricela PradoCardiothoracic Surgery (I.P.-G., A.A.G., J.A.A., T.-H.W., N.V., M.P., Y.Z., L.D., I.K.), Stanford University School of Medicine, Stanford University, CA.
Yuan ZhangCardiothoracic Surgery (I.P.-G., A.A.G., J.A.A., T.-H.W., N.V., M.P., Y.Z., L.D., I.K.), Stanford University School of Medicine, Stanford University, CA.
Logan DunkenbergerCardiothoracic Surgery (I.P.-G., A.A.G., J.A.A., T.-H.W., N.V., M.P., Y.Z., L.D., I.K.), Stanford University School of Medicine, Stanford University, CA.
Joost P G SluijterDepartment of Cardiology, Division Heart and Lungs (R.G.C.M., M.H., J.P., J.P.G.S., F.W.A.), University Medical Center Utrecht, University of Utrecht, The Netherlands.
Karim SallamCardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Folkert W AsselbergsDepartment of Cardiology, Division Heart and Lungs (R.G.C.M., M.H., J.P., J.P.G.S., F.W.A.), University Medical Center Utrecht, University of Utrecht, The Netherlands.
Mark MercolaCardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Ioannis KarakikesCardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Cardiovascular Institute of the South · USUtrecht University · NLStanford University · USMACOM (United States) · USUniversity Medical Center Groningen · NL

Funding

Project 3 (Mercola)P01HL141084 · NHLBI · STANFORD UNIVERSITY · PI Joseph C. Wu · 2019 to 2026
$21.1M
Human Induced Pluripotent Stem Cells for Cardiovascular Disease ModelingR01HL113006 · NHLBI · STANFORD UNIVERSITY · PI WU, JOSEPH C. · 2012 to 2025
$6.8M
MicroRNA Control of Dilated CardiomyopathyR01HL130840 · NHLBI · STANFORD UNIVERSITY · PI MARK MERCOLA, Shankar Subramaniam · 2016 to 2026
$4.6M
Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicineR01HL139679 · NHLBI · STANFORD UNIVERSITY · PI Ioannis Karakikes · 2018 to 2026
$4.2M
Role of miR25 in Heart FailureR01HL128072 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI HAJJAR, ROGER J., MERCOLA, MARK · 2015 to 2018
$2.5M
The Role of 3-Dimensional Genome Integrity In Cardiac LaminopathiesR01HL150414 · NHLBI · STANFORD UNIVERSITY · PI KARAKIKES, IOANNIS · 2020 to 2023
$2.1M
Small Molecule NOTCH Inhibitors for the treatment of pulmonary hypertensionR01HL132225 · NHLBI · STANFORD UNIVERSITY · PI MERCOLA, MARK, THISTLETHWAITE, PATRICIA A · 2016 to 2019
$1.7M
miR-152: A Novel Regulator of Diabetic CardiomyopathyR00HL104002 · NHLBI · STANFORD UNIVERSITY · PI KARAKIKES, IOANNIS · 2017 to 2019
$893k
Kinetic Imaging Cytometer (KIC) for High Throughput Studies of Cellular PhysiologyS10OD030264 · OD · STANFORD UNIVERSITY · PI MERCOLA, MARK · 2021 to 2021
$528k
American Heart Association-American Stroke Association 17IRG33410532American Heart Association-American Stroke Association 19POST34380920NHLBI NIH HHS P01 HL141084NHLBI NIH HHS R00 HL104002NHLBI NIH HHS R01 HL113006NHLBI NIH HHS R01 HL128072NHLBI NIH HHS R01 HL130840NHLBI NIH HHS R01 HL132225NHLBI NIH HHS R01 HL139679NHLBI NIH HHS R01 HL150414NIH HHS S10 OD030264
6 · The paper itself

Abstract

backgroundPhospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies.

methodsWe used single-cell RNA sequencing to uncover PLN R14del disease mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We used both 2-dimensional and 3-dimensional functional contractility assays to evaluate the impact of modulating disease-relevant pathways in PLN R14del hiPSC-CMs.

resultsModeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro. Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X. PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis.

conclusionsTogether, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.

Indexed as

Disease SusceptibilitySequence DeletionUnfolded Protein ResponseAdaptation, PhysiologicalBiomarkersCalcium-Binding ProteinsCardiomyopathiesCardiomyopathy, DilatedCulture Media, ConditionedDisease ManagementGene Expression ProfilingGenetic Predisposition to DiseaseHumansInduced Pluripotent Stem CellsMolecular Targeted TherapyMyocardial ContractionBiomarkersCalcium-Binding ProteinsCulture Media, ConditionedPhospholambancardiomyopathy, dilatedinduced pluripotent stem cellsmodels, biologicalphospholambansequence analysis, RNAunfolded protein response

Identifiers

PMID33928785
PMCPMC8667423
OpenAlexW3159185597

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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.