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American Heart Association

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Final ID: MDP1355

Protein Arginin Deiminase 4 Deficiency Prevents Streptozotocin-induced Diabetic Cardiomyopathy and Heart Failure with Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation

Abstract Body (Do not enter title and authors here): Background: Heart failure (HF) is a complication of Type 1 diabetes mellitus (T1D) causing high mortality. In T1D activated neutrophils overproduce peptidyl arginine deiminase 4 (PAD4).
Aim: Evaluate the role of PAD4 in the pathobiology of HF development in T1D.
Methods: T1D was induced in PAD4-/- and wild type (WT) mice by i.p. injection of 55 mg/kg of Streptozotocin for 5 days. Echocardiography, lung wet-to-dry ratio and exercise intolerance were performed after 8 weeks to evaluate cardiac structural and functional changes. Cardiac collagen content was assessed by picrosirius green staining, levels of neutrophil extracellular traps (NETs) by co-location of Ly6G+, and H3Cit+ signal in tissue and inflammasome activation by protein aggregates of the inflammasome adaptor ASC in neutrophils determined by immunofluorescence.
Results: PAD4 deficiency did not affect onset or severity of T1D. T1D WT but not T1D PAD4-/- mice showed a significantly increased proportion of ASC speck+ neutrophils (13.8± 4% vs. 3.3±3.1%; n=5; p=0.007). This resulted in elevated IL-1β levels both in plasma (21.7±7pg/ml vs. 11.4±1pg/ml; n=8; p=0.001) and cardiac tissue (0.08±0.002pg/ml vs. 0.06±0.001pg/ml; n=8/6, p=0.001) of T1D-WT mice. T1D-PAD4-/- mice showed reduced cardiac damage (Troponin I: 58±11pg/mL vs. 91.3±37pg/mL; n=12; p=0.005), collagen deposition (1.2±0.5% vs. 3.3±1.3%; n=6; p=0.008) and tissue levels of transforming growth factor-β (0.23±0.03 vs. 0.33±0.04 ng/L). Echocardiography demonstrated preservation of both systolic (Ejection fraction: 63.8±5.4 vs. 43.7±11.4 %; n=8; p=0.001) and diastolic (E/E’: -19.6±4 vs. -29.9±9; n=10; p=0.004) function with PAD4 deletion and reduced clinical HF parameters (Lung wet/dry ratio: 4.1±0.5 vs. 5.9±0.9; n=8; p=0.001; time to fatigue: 28.1±10min. vs. 7.6±4 min.;n=10,p=<0.0001). Flow cytometry analysis showed significantly reduced levels of infiltrating neutrophils (42±2% vs. 52± 3% Ly6G+ of CD11b+CD45+ events; n=8, p=0.02) in the myocardium and histological analysis showed significantly reduced cardiac NET deposition in T1D- PAD4-/- mice (1.1±0.4% vs. 10.2±2.2% H3Cit+ of LV section; n=5, p=0.008).
Conclusion: We show, that T1D primes neutrophils for NLRP3 Inflammasome assembly and IL-1β release in a PAD4 dependent manner. Increased cardiac neutrophil infiltration, inflammasome assembly and NET deposition drive profibrotic cardiac remodeling and HF in T1D. Our data suggest PAD4 as a promising target for primary cardiac prevention in T1D.
  • Schommer, Nicolas  ( UHZ Freiburg Bad Krozingen , Freiburg , Germany )
  • Sheehy, Casey  ( Boston Children's Hospital , Boston , Massachusetts , United States )
  • Van Bruggen, Stijn  ( KU Leuven , Leuven , Belgium )
  • Jarrot, Pierre-andré  ( Boston Children's Hospital , Boston , Massachusetts , United States )
  • Chan, William  ( Boston Children's Hospital , Boston , Massachusetts , United States )
  • Westermann, Dirk  ( UHZ Freiburg Bad Krozingen , Freiburg , Germany )
  • Wagner, Denisa  ( Boston Children's Hospital , Boston , Massachusetts , United States )
  • Heger, Lukas  ( UHZ Freiburg Bad Krozingen , Freiburg , Germany )
  • Author Disclosures:
    Nicolas Schommer: DO NOT have relevant financial relationships | Casey Sheehy: No Answer | Stijn Van Bruggen: No Answer | Pierre-André Jarrot: DO NOT have relevant financial relationships | William Chan: No Answer | Dirk Westermann: No Answer | Denisa Wagner: DO NOT have relevant financial relationships | Lukas Heger: DO NOT have relevant financial relationships
Meeting Info:

Scientific Sessions 2024

2024

Chicago, Illinois

Session Info:

Anemia in Heart Failure

Monday, 11/18/2024 , 12:50PM - 02:15PM

Moderated Digital Poster Session

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