Evidence map›Paper›PMID 40929060›Full record

ArticlePloS one2025

Peptidylarginine deiminase 4 deficiency alleviates hypoxia/reoxygenation-induced cardiomyocyte injury.

Matthias Mand, Michelle Holthaus, Helmut R Lieder, Petra Kleinbongard, Lenard Conradi, Thorsten Wahlers, Adnana Paunel-Görgülü

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Article in PloS one, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing 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

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

3 citing papers in PubMed.

  1. Review
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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.

Matthias MandDepartment of Cardiac Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Michelle HolthausDepartment of Cardiac Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Helmut R LiederCardioprotection Unit, Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, University of Duisburg-Essen, Essen, Germany.
Petra KleinbongardCardioprotection Unit, Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, University of Duisburg-Essen, Essen, Germany.ORCID 0000-0003-3576-3772
Lenard ConradiDepartment of Cardiac Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Thorsten WahlersDepartment of Cardiac Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.ORCID 0000-0002-8437-4119
Adnana Paunel-GörgülüDepartment of Cardiac Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.ORCID 0000-0001-6467-3544

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundCardiac ischemia reperfusion (I/R) injury is a serious consequence of reperfusion therapy for myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the citrullination of proteins. In previous studies, PAD4 inhibition protected distinct organs from I/R injury by preventing the formation of neutrophil extracellular traps (NETs) and attenuating inflammatory responses. Here, we hypothesized that cardiomyocyte PAD4 expression may play a role in acute I/R injury.

methodsInfarct size was determined in isolated pressure constant-perfused hearts from WT and PAD4-deficient (PAD4-/-) mice. Additionally, extracellular reactive oxygen species (ROS) and cell viability were quantified in freshly isolated adult cardiomyocytes exposed to hypoxia followed by reoxygenation (H/R). Resistance to oxidative stress was proven in both genotypes by treatment of neonatal cardiomyocytes with hydrogen peroxide. Moreover, intracellular ROS formation, ATP production, mitochondrial membrane polarisation, caspase-3 activation, and cell viability were quantified after hypoxia followed by 4 h and 20 h of reoxygenation, respectively. The PAD4-specific inhibitor GSK484 was added before H/R or at reperfusion in certain experiments.

resultsInfarct size was smaller in PAD4-/- hearts following I/R when compared to the WT. Similarly, the viability of adult and neonatal PAD4-/- cardiomyocytes was better preserved after H/R, accompanied by reduced ROS formation. PAD4 deficiency maintained mitochondrial integrity and protected neonatal cardiomyocytes against apoptosis. However, these cells did not exhibit resistance to hydrogen peroxide-induced cell death, indicating an unaltered antioxidative state. Whereas pharmacological PAD4 inhibition by GSK484 before H/R sustained intracellular ATP levels in WT cardiomyocytes, administration of GSK484 at reoxygenation did not. However, GSK484 significantly improved cardiomyocyte metabolic activity, regardless of the time of administration.

conclusionsOur study is the first to demonstrate that PAD4 expression in cardiomyocytes contributes to H/R injury independent of systemic immune responses and NETs. Consequently, PAD4 may serve as a therapeutic target to alleviate I/R injury.

Indexed as

HydrolasesMyocardial Reperfusion InjuryMyocytes, CardiacAnimalsApoptosisCaspase 3Cell HypoxiaCell SurvivalMaleMiceMice, Inbred C57BLMice, KnockoutMyocardial InfarctionOxidative StressOxygenProtein-Arginine DeiminasesCaspase 3HydrolasesOxygenpeptidylarginine deiminase 4, mouseProtein-Arginine DeiminasesProtein-Arginine Deiminase Type 4Reactive Oxygen Species

Identifiers

PMID40929060
PMCPMC12422421

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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.