Reducing Abdominal Aortic Aneurysm Progression by Blocking Neutrophil Extracellular Traps Depends on Thrombus Formation

Neutrophil Extracellular Traps in Cardiovascular and Aortic Disease: A Narrative Review on Molecular Mechanisms and Therapeutic Targeting

“…Furthermore, we and others reported that the specific PADI4 inhibitors YW3-56 or GSK484 reduced aorta rupture [92] and prevented aneurysm progression [91,97], which closely matches the clinical setting and therapeutic demand. Importantly, we found that upstream inhibition of NET formation by GSK484 or Nox2ds-tat inhibitory peptide was more effective in controlling AAA disease than downstream interference by dismantling NETs with DNase 1 or by inactivating histone toxicity with HIPe [97]. Our study also established a therapeutic link between NETs and thrombosis in AAA, as NET inhibition was only successful in mice with intramural thrombus formation in aneurysms [97].…”

“…Use of the pan-PAD inhibitor Cl-amidine significantly attenuated AAA formation in mice [90]. Furthermore, we and others reported that the specific PADI4 inhibitors YW3-56 or GSK484 reduced aorta rupture [92] and prevented aneurysm progression [91,97], which closely matches the clinical setting and therapeutic demand. Importantly, we found that upstream inhibition of NET formation by GSK484 or Nox2ds-tat inhibitory peptide was more effective in controlling AAA disease than downstream interference by dismantling NETs with DNase 1 or by inactivating histone toxicity with HIPe [97].…”

“…Importantly, we found that upstream inhibition of NET formation by GSK484 or Nox2ds-tat inhibitory peptide was more effective in controlling AAA disease than downstream interference by dismantling NETs with DNase 1 or by inactivating histone toxicity with HIPe [97]. Our study also established a therapeutic link between NETs and thrombosis in AAA, as NET inhibition was only successful in mice with intramural thrombus formation in aneurysms [97]. Notably, two AAA mouse models were used in our study: angiotensin II (Ang-II) administration to ApoE deficient mice or peri-adventitial application of porcine pancreatic elastase in wildtype mice.…”

“…Upstream inhibitors act by disrupting the NET formation process. These include Cl-amidine [60,98], GSK484 [91,97,99], and YW3-56 [92], which inhibit peptidylarginine deiminase 4 (PADI4), thus preventing histone citrullination and NET release. Inhibitors of the NADPH oxidase 2 (Nox2) pathway, such as diphenyleneiodonium chloride (DPI) [100], GSK2795039 [100], and Nox2ds-tat [97], block ROS generation and subsequent granule release, which is essential for chromatin decondensation.…”

“…These include Cl-amidine [60,98], GSK484 [91,97,99], and YW3-56 [92], which inhibit peptidylarginine deiminase 4 (PADI4), thus preventing histone citrullination and NET release. Inhibitors of the NADPH oxidase 2 (Nox2) pathway, such as diphenyleneiodonium chloride (DPI) [100], GSK2795039 [100], and Nox2ds-tat [97], block ROS generation and subsequent granule release, which is essential for chromatin decondensation. Sivelestat [101] and low-molecular weight heparin (LMWH) [102] target neutrophil elastase (NE) and the release of the granular components.…”