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Inhibition of Neutrophil Extracellular Traps Reveals their Differential Role in the Pathogenesis of Abdominal Aortic Aneurysms in Distinct Mouse Models

1Department of General Surgery: Division of Vascular Surgery, Medical University of Vienna, Vienna, Austria, 2Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany, 3Molecular Vascular Medicine Group, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden, 4Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Faculty of Medicine and Health, Leeds, United Kingdom, 5Leeds Vascular Institute, Leeds General Infirmary, Leeds, United Kingdom

Abstract Number: OC 28.1

Meeting: ISTH 2021 Congress

Theme: Vascular Biology » Blood Cells and Vessel Wall

Background: Neutrophil extracellular traps (NETs), which are composed of expelled DNA and proteins, have been implicated in the pathogenesis of abdominal aortic aneurysms (AAA), where they have been found in the intraluminal thrombus and the aortic adventitia of AAA patients.

Aims: This study investigates the therapeutic potential of distinct NET inhibitors on established AAA disease in mice by targeting major effector molecules of NET formation: PAD4 and NADPH oxidase 2 (Nox2).

Methods: AAAs are induced in two mouse models and monitored by ultrasound: (1) in ApoE KO mice by subcutaneous implantation of osmotic pumps which release angiotensin II over 28 days; (2) in C57BL6/J mice by peri-adventitial elastase application to the infrarenal abdominal aorta. The aneurysms develop by day 8 and 4, respectively, then the animals are stratified and receive daily intravenous injections with PBS (as control) or anti-NET therapy: GSK484 (PAD4 inhibitor), or Nox2ds-tat (Nox2 inhibitor).

Results: In both models, immunofluorescence staining of aneurysmatic aortas prior to treatment showed the presence of NETs. In the ApoE KO model, targeting NETs resulted in a lower AAA progression by d28 compared to control (GSK484: n=8/group, 175% vs 275% mean aortic volume growth, p=0.040; Nox2ds-tat: n=6/group, 196.9% vs 345%, p=0.044). However, in the elastase model neither treatment had a significant effect on AAA progression.

Conclusions: These results indicate that NETs may have different involvement in the two mouse models, with a potentially prominent role in AAA progression in the ApoE KO model. While the latter model mimics the hallmarks of hyperlipidemia and hypertension in AAA disease, the elastase model is based on an acute inflammatory insult. Thus, we are next evaluating the effects of these inhibitors on AAA initiation in the elastase model where NETs might play a role at an earlier stage of pathogenesis.

To cite this abstract in AMA style:

Ibrahim N, Bleichert S, Klopf J, Knöbl V, Brandau A, Busch A, Bailey M, Eilenberg W, Neumayer C, Brostjan C. Inhibition of Neutrophil Extracellular Traps Reveals their Differential Role in the Pathogenesis of Abdominal Aortic Aneurysms in Distinct Mouse Models [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/inhibition-of-neutrophil-extracellular-traps-reveals-their-differential-role-in-the-pathogenesis-of-abdominal-aortic-aneurysms-in-distinct-mouse-models/. Accessed November 29, 2023.

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