Evidence map›Paper›PMID 40948130›Full record

ArticleCirculation research2025

Targeting Cardiomyocyte PCNA and POLD1 Prevents Pathologic Myocardial Hypertrophy.

Soumojit Pal, Michael S Glennon, Benjamin R Nixon, Ethan J Chetkof, Puneeth Shridhar, Chintha M Kathiresan, Morgan B Glasser, Christina J Waldron, Lanping Guo, Nicolas G Clavere and 3 more

Abstract read
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In one paragraph

Article in Circulation research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
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

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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

2 citing papers in PubMed.

  1. Article
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Soumojit PalDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).ORCID 0000-0002-3873-0450
Michael S GlennonDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).ORCID 0009-0006-2898-6731
Benjamin R NixonDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Ethan J ChetkofDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Puneeth ShridharDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Chintha M KathiresanDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Morgan B GlasserDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Christina J WaldronDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).ORCID 0000-0003-0286-6599
Lanping GuoDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Nicolas G ClavereDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Dipanjan BanerjeeDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).ORCID 0000-0003-3331-958X
Jenny H KimDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).
Jason R BeckerDivision of Cardiology, Department of Medicine and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (S.P., M.S.G., B.R.N., E.J.C., P.S., C.M.K., M.B.G., C.J.W., L.G., N.G.C., D.B., J.H.K., J.R.B.).ORCID 0000-0002-2107-8179

Funding

MDM2-HIF signaling in pathological ventricular remodelingR01HL167955 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Jason Becker · 2024 to 2026
$2.2M
Cell State Specific Modifiers of Pathological Cardiac RemodelingR01HL136824 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BECKER, JASON · 2017 to 2021
$2.0M
Cardiomyocyte selective modulation of natriuretic peptide signaling in cardiomyopathyR01HL169784 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Jason Becker · 2024 to 2026
$1.9M
MDM2-HIF signaling in pathological ventricular remodelingR56HL160890 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BECKER, JASON · 2022 to 2022
$597k
NHLBI NIH HHS R01 HL136824NHLBI NIH HHS R01 HL167955NHLBI NIH HHS R01 HL169784NHLBI NIH HHS R56 HL160890
6 · The paper itself

Abstract

backgroundActivation of cell cycle regulatory pathways has been detected during pathological cardiomyocyte growth. However, it has remained unclear whether DNA synthesis pathways play a direct role in cardiomyocyte hypertrophy. We previously discovered in a mouse model of hypertrophic cardiomyopathy that there was increased DNA synthesis, which led to cardiomyocyte endoreplication and replication stress-induced DNA damage. We hypothesized that targeting cardiomyocyte endoreplication pathways could reduce pathological myocardial hypertrophy.

methodsWe utilized murine models of hypertrophic cardiomyopathy secondary to mutations in cardiac Mybpc3 (myosin-binding protein C3)

resultsWe discovered that p21 protein peaked during the early stages of hypertrophic growth in both murine hypertrophic cardiomyopathy models and a pressure overload hypertrophy model. Using genetic manipulation of p21 expression, we discovered that cardiomyocyte endoreplication and hypertrophic growth were negatively correlated with p21 expression. Mechanistically, we discovered that p21 bound to PCNA (proliferating cell nuclear antigen), which led to a reduction of PCNA binding to POLD1 (DNA polymerase delta 1). Directly targeting PCNA or POLD1 prevented cardiomyocyte DNA synthesis and hypertrophic cardiomyocyte growth. Cardiomyocyte-selective overexpression of p21 using an adeno-associated virus vector reduced long-term pathological left ventricular hypertrophy and improved diastolic function in a preclinical murine model of hypertrophic cardiomyopathy (Myh6

conclusionsOur results demonstrate that PCNA-POLD1-mediated cardiomyocyte endoreplication drives hypertrophic cardiomyocyte growth, and p21 serves as a negative regulator of this process. Targeting these pathways demonstrates therapeutic potential in preventing pathological myocardial hypertrophy.

Indexed as

CardiomegalyCardiomyopathy, HypertrophicDNA Polymerase IIIMyocytes, CardiacProliferating Cell Nuclear AntigenAnimalsCarrier ProteinsCyclin-Dependent Kinase Inhibitor p21Disease Models, AnimalHumansMaleMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMyosin Binding Protein CCarrier ProteinsCdkn1a protein, mouseCyclin-Dependent Kinase Inhibitor p21DNA Polymerase IIIMyh6 protein, mouseMyosin Binding Protein CMyosin Heavy ChainsProliferating Cell Nuclear Antigencardiomyopathy, hypertrophicdisease models, animalendoreduplicationheart failurehypertrophymyocytes, cardiacpolyploidy

Identifiers

PMID40948130
PMCPMC12509454

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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.