ArticleEuropean heart journal2025
Neutrophil extracellular traps and peptidylarginine deiminase 4-mediated inflammasome activation link diabetes to cardiorenal injury and heart failure.
Article in European heart journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Identification of IL1RN, MUC1, and SERPINA1 as key NET-related biomarkers in ulcerative colitis-associated intestinal fibrosis via bioinformatics and experimental validation.BMC gastroenterology · 2026Article
- MMP8 Promotes NETosis in Gestational Diabetes Mellitus.Antioxidants (Basel, Switzerland) · 2026Article
- Comprehensive Evaluation of YJ-2 as a PAD4 Inhibitor in Alleviating Ischemic Brain Injury: From NETs-Induced Neurotoxicity to In Vivo Neuroprotection.CNS neuroscience & therapeutics · 2026Article
- Metabolic Reprogramming-Driven Cardiovascular Immune Damage: From Glyco-Lipotoxicity and Epigenetic Memory to Multidimensional Cross-Organ Communication Networks.International journal of molecular sciences · 2026Review
- Differential presence of neutrophil extracellular traps in serum vs plasma of patients with critical limb-threatening ischemia.Research and practice in thrombosis and haemostasis · 2026Article
- Total Saponins from Rhizoma Panacis Majoris Promote Wound Healing in Diabetic Rats by Regulating Inflammatory Dysregulation.International journal of molecular sciences · 2026Article
- Mechanistic interplay between extracellular vesicles and neutrophil extracellular traps: unveiling the "sterile inflammation" cascade in obesity-induced diabetes progression.Frontiers in immunology · 2026Review
- Inflammatory responses driven by neutrophil extracellular traps in cardiovascular diseases: molecular mechanisms, emerging biomarkers, and therapeutic targets.Frontiers in immunology · 2026Review
- Study on the pro-inflammatory injury of neutrophil extracellular traps in gouty nephropathy.Frontiers in immunology · 2026Review
- Elevated Serum LL37 and Myeloperoxidase-DNA Complexes Predict the Progression of Diabetic Kidney Disease.Kidney diseases (Basel, Switzerland)Article
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Authors and funding
13 authors.
Funding
Abstract
BACKGROUND AND
aimsDiabetes is associated with increased risk of cardiovascular and renal disease. This study investigated the role of peptidylarginine deiminase 4 (PAD4), neutrophil extracellular traps (NETs), and inflammasome activation in diabetic cardiomyopathy (DCM) and kidney disease (DKD).
methodsEndomyocardial biopsies (EMB) from heart failure (HF) patients (n = 20) with or without diabetes were stained for NETs. Wild-type (WT) and PAD4⁻/⁻ mice were subjected to streptozotocin (STZ)-induced diabetes and cardiac function, blood glucose, body weight, and exercise tolerance were assessed longitudinally. NETosis and ASC specks were evaluated in mouse and human neutrophils. Cardiac and renal fibrosis was assessed by Sirius Red/Fast Green staining. Confocal microscopy, ELISA, and flow cytometry were used to quantify NETs, IL-1β, von Willebrand factor (VWF), cytokine transforming growth factor beta-1 (TGF-β1), and neutrophil infiltration.
resultsMyocardial NET burden was increased in HF patients with diabetes. High glucose triggered inflammasome activation in human neutrophils. After STZ, PAD4⁻/⁻ and WT mice developed hyperglycaemia and weight loss, yet only WT neutrophils showed increased NETosis and ASC speck formation. Only diabetic WT mice exhibited elevated IL-1β and VWF levels, impaired cardiac function, reduced exercise tolerance, and pulmonary oedema; PAD4⁻/⁻ mice were protected. Wild-type diabetic hearts and kidneys showed greater fibrosis, neutrophil infiltration, NETs, and TGF-β1 levels. Kidney injury in WT mice was reflected by albuminuria and renal fibrosis, whereas PAD4⁻/⁻ mice preserved renal function.
conclusionsDiabetes promotes neutrophil inflammasome activation and NETosis, driving cardiac and renal inflammation and fibrosis. Peptidylarginine deiminase 4 deficiency prevents heart failure and preserves kidney function in experimental diabetes.
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