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

Abstract

Neutrophil 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

Inhibition of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Rupture in Mice

“…Of note, Wolf Eilenberg et al (40) demonstrated that histone citrullination is a novel biomarker in AAA and PAD4 inhibitor GSK484 attenuated Ang II-induced AAA. However, how the NETs affected AAA was unexplored.…”

Kynurenic Acid and Its Synthetic Derivatives Protect Against Sepsis-Associated Neutrophil Activation and Brain Mitochondrial Dysfunction in Rats

“…Although numerous variable components of NETs have been identified, some structural elements of NETs are consistent and comprehensive biomarkers ( 13 ). Levels of many circulating NET markers (including plasma MPO, CitH3, circulating cell-free DNA-histone complexes) and NET inducers (IL-1β and interleukin-8; IL-8) increase under various inflammatory conditions ( 36 , 37 ). Among these, CitH3 is highly specific to NET formation, and it was also suggested as a therapeutic target in experimental models of sepsis ( 38 , 39 ).…”

Neutrophils as Regulators and Biomarkers of Cardiovascular Inflammation in the Context of Abdominal Aortic Aneurysms

“…Citrullinated histones and cell-free DNA were found to be elevated in the plasma and tissue of AAA patients [ 96 , 126 , 128 ]. Our recently reported study focused on NET-specific histone citrullination and biomarker analysis of citrullinated histone H3 (citH3) in AAA disease [ 130 ]. Plasma levels of citH3 were found to be considerably higher in AAA patients compared to healthy controls and remained significant for AAA presence in multivariable analysis.…”

“…Of note, further expansion of an established experimental AAA was prevented in mice treated with a NET inhibitor targeting histone citrullination. Therefore, it seems that citH3 represents a promising AAA biomarker and histone citrullination a potential therapeutic target to control AAA disease progression [ 130 ]. We and others found the highest concentration of NET components in the adventitia, but also the ILT showed depositions of citrullinated histones [ 126 , 128 , 130 ].…”

“…Additionally, higher levels of TNF-α were shown in asymptomatic AAA patients compared to patients with either symptomatic AAA or aneurysm rupture [ 132 , 133 , 134 , 135 ]. We recently showed that IL-1β, which was reported to trigger NET formation, was found to be significantly increased in tissue-conditioned medium of AAA patients, but not in the tissue-conditioned medium of ILT compared to aortas from transplant donors [ 130 ]. Neutrophil chemotaxis to the inflammatory AAA site is highly regulated by potent chemoattractants such as IL-8 [ 48 ].…”