• Transl Res · Jul 2021

    Histone citrullination as a novel biomarker and target to inhibit progression of abdominal aortic aneurysms.

    • Wolf Eilenberg, Branislav Zagrapan, Sonja Bleichert, Nahla Ibrahim, Viktoria Knöbl, Annika Brandau, Luca Martelanz, Marie-Therese Grasl, Hubert Hayden, Paimann Nawrozi, Renata Rajic, Charlotte Häusler, Alexandros Potolidis, Nawa Schirwani, Andreas Scheuba, Johannes Klopf, Peter Teubenbacher, Markus P Weigl, Patrick Kirchweger, Dietrich Beitzke, Alexander Stiglbauer-Tscholakoff, Adelheid Panzenböck, Irene Lang, Lisa-Marie Mauracher, Lena Hell, Ingrid Pabinger, Marc A Bailey, ScottD Julian ADJALeeds Vascular Institute, Leeds General Infirmary, Leeds, United Kingdom; Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Faculty of Medicine and Health, Leeds, United Kingdom., Lars Maegdefessel, Albert Busch, Ihor Huk, Christoph Neumayer, and Christine Brostjan.
    • Department of General Surgery: Division of Vascular Surgery, Medical University of Vienna, Vienna, Austria.
    • Transl Res. 2021 Jul 1; 233: 324632-46.

    AbstractNeutrophil extracellular traps (NETs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAAs). This study has addressed the notion that NET components might serve as AAA biomarkers or novel targets of AAA therapy. Thus, parameters of neutrophil activation and NET formation were measured in plasma. Their diagnostic marker value was explored in 41 AAA patients and 38 healthy controls. The NET parameter citrullinated histone H3 (citH3) was then validated in 63 AAA patients and 63 controls matched for cardiovascular disease. The prognostic marker potential was investigated in 54 observation periods of AAA growth over 6 months. NETs were further assessed in conditioned medium and sections of aortic tissue. CitH3 was found to be increased in blood (median 362 vs 304 ng/mL, P = 0.004) and aortic tissue (50 vs 1.5 ng/mg, P < 0.001) of AAA patients compared to healthy controls and accumulated in the intraluminal thrombus (629 ng/mg). The diagnostic potential of citH3 ranged at 0.705 area under the ROC curve (AUROC) and was validated with the independent sample set. Furthermore, plasma citH3 predicted AAA growth over the next 6 months (AUROC: 0.707, P = 0.015) and dropped significantly after surgical aneurysm repair. In an angiotensin II - based mouse model of experimental AAA, an inhibitor of histone citrullination was applied to block NET formation and AAA progression. Of note, further growth of an established aneurysm was prevented in mice treated with the NET inhibitor (P = 0.040). In conclusion, histone citrullination represents a promising AAA biomarker and potential therapeutic target to control disease progression.Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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