{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:22:04Z","timestamp":1793164924547,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670400"],"award-info":[{"award-number":["81670400"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004806","name":"Fok Ying Tong Education Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004806","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold> Neutrophil infiltration plays an important role in the initiation and development of abdominal aortic aneurysm (AAA). Recent studies suggested that neutrophils could release neutrophil extracellular traps (NETs), leading to tissue injury in cardiovascular diseases. However, the role of NETs in AAA is elusive. This study aimed to investigate the role and underlying mechanism of NETs in AAA development.<\/jats:p><jats:p><jats:bold>Methods and Results:<\/jats:bold> An angiotensin II (Ang II) infusion-induced AAA model was established to investigate the role of NETs during AAA development. Immunofluorescence staining showed that citrullinated histone 3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) (NET marker) expressions were significantly increased in Ang II-infused <jats:italic>ApoE<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. The circulating double-stranded DNA (dsDNA) level was also elevated, indicating the increased NET formation during AAA. PAD4 inhibitor YW3-56 inhibited Ang II-induced NET formation. Disruption of NET formation by YW3-56 markedly reduced Ang II-induced AAA rupture, as revealed by decreased aortic diameter, vascular smooth muscle cell (VSMC) apoptosis, and elastin degradation. Apoptosis of VSMC was evaluated by TUNEL staining and Annexin V-FITC\/PI staining through flow cytometry. Western blot and inhibition experiments revealed that NETs induced VSMC apoptosis <jats:italic>via<\/jats:italic> p38\/JNK pathway, indicating that PAD4-dependent NET formation played an important role in AAA.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> This study suggests that PAD4-dependent NET formation is critical for AAA rupture, which provides a novel potential therapeutic strategy for AAA disease.<\/jats:p>","DOI":"10.3389\/fcvm.2021.676612","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T04:50:57Z","timestamp":1627620657000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Inhibition of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Rupture in Mice"],"prefix":"10.3389","volume":"8","author":[{"given":"Ming","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guomin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoqi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aijuan","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"B1","first-page":"538","article-title":"Abdominal aortic aneurysm","volume":"91","author":"Keisler","year":"2015","journal-title":"Am Fam Physician."},{"key":"B2","doi-asserted-by":"publisher","first-page":"296","DOI":"10.3238\/arztebl.2012.0727","article-title":"Ruptured abdominal aortic aneurysm","volume":"73","author":"Tchana-Sato","year":"2018","journal-title":"Rev Med Liege."},{"key":"B3","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1161\/CIRCRESAHA.118.312439","article-title":"Pharmacologic management of aneurysms","volume":"124","author":"Lindeman","year":"2019","journal-title":"Circ Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e003557","DOI":"10.1161\/CIRCIMAGING.115.003557","article-title":"Transthoracic echocardiography provides important long-term prognostic information in selected patients undergoing endovascular abdominal aortic repair","volume":"9","author":"O'Driscoll","year":"2016","journal-title":"Circ Cardiovasc Imaging."},{"key":"B5","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nrcardio.2013.196","article-title":"Endovascular treatment of abdominal aortic aneurysms","volume":"11","author":"Buck","year":"2014","journal-title":"Nat Rev Cardiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/nrcardio.2010.180","article-title":"Pathophysiology and epidemiology of abdominal aortic aneurysms","volume":"8","author":"Nordon","year":"2011","journal-title":"Nat Rev Cardiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1089\/ars.2013.5507","article-title":"Hemodynamic regulation of reactive oxygen species: implications for vascular diseases","volume":"20","author":"Raaz","year":"2014","journal-title":"Antioxid Redox Signal."},{"key":"B8","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1038\/nri2415","article-title":"The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models","volume":"8","author":"Weber","year":"2008","journal-title":"Nat Rev Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1161\/CIRCULATIONAHA.108.832972","article-title":"Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm","volume":"119","author":"Pagano","year":"2009","journal-title":"Circulation."},{"key":"B10","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1093\/cvr\/cvp048","article-title":"Mediators of neutrophil recruitment in human abdominal aortic aneurysms","volume":"82","author":"Houard","year":"2009","journal-title":"Cardiovasc Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1161\/CIRCULATIONAHA.104.517391","article-title":"Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation","volume":"112","author":"Eliason","year":"2005","journal-title":"Circulation."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil extracellular traps kill bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1134\/S0006297914120025","article-title":"Neutrophil extracellular traps: mechanisms of formation and role in health and disease","volume":"79","author":"Vorobjeva","year":"2014","journal-title":"Biochemistry (Mosc)."},{"key":"B14","doi-asserted-by":"publisher","first-page":"pe11","DOI":"10.1126\/stke.3792007pe11","article-title":"Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, cell death","volume":"2007","author":"Steinberg","year":"2007","journal-title":"Sci STKE."},{"key":"B15","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41423-018-0024-0","article-title":"NETosis, complement, and coagulation: a triangular relationship","volume":"16","author":"de Bont","year":"2019","journal-title":"Cell Mol Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1159\/000206974","article-title":"Regulation of extracellular chromatin release from neutrophils","volume":"1","author":"Neeli","year":"2009","journal-title":"J Innate Immun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1089\/152308602753625852","article-title":"Assembly and activation of the neutrophil NADPH oxidase in granule membranes","volume":"4","author":"Karlsson","year":"2002","journal-title":"Antioxid Redox Signal."},{"key":"B18","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1161\/ATVBAHA.117.309897","article-title":"Novel role of IL (Interleukin)-1beta in neutrophil extracellular trap formation and abdominal aortic aneurysms","volume":"38","author":"Meher","year":"2018","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1660","DOI":"10.1161\/ATVBAHA.116.307786","article-title":"Neutrophil proteases promote experimental abdominal aortic aneurysm via extracellular trap release and plasmacytoid dendritic cell activation","volume":"36","author":"Yan","year":"2016","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1038\/s41586-019-1167-6","article-title":"Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death","volume":"569","author":"Silvestre-Roig","year":"2019","journal-title":"Nature."},{"key":"B21","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1093\/cvr\/cvs263","article-title":"Deficiency of cathepsin S attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice","volume":"96","author":"Qin","year":"2012","journal-title":"Cardiovasc Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"25941","DOI":"10.1074\/jbc.M112.375725","article-title":"Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity","volume":"287","author":"Wang","year":"2012","journal-title":"J Biol Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/s41419-019-1757-0","article-title":"Hypoxia inducible factor 1alpha in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment","volume":"10","author":"Qi","year":"2019","journal-title":"Cell Death Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1161\/CIRCRESAHA.116.308895","article-title":"Age-associated sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm","volume":"119","author":"Chen","year":"2016","journal-title":"Circ Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"52687","DOI":"10.3791\/52687","article-title":"Simplified human neutrophil extracellular traps (NETs) isolation and handling","volume":"98","author":"Najmeh","year":"2015","journal-title":"J Vis Exp"},{"key":"B26","doi-asserted-by":"publisher","first-page":"590622","DOI":"10.3389\/fimmu.2020.590622","article-title":"Neutrophil extracellular traps promote aberrant macrophages activation in behcet's disease","volume":"11","author":"Li","year":"2020","journal-title":"Front Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"106055","DOI":"10.1016\/j.intimp.2019.106055","article-title":"Inhibition of peptidyl arginine deiminase-4 protects against myocardial infarction induced cardiac dysfunction","volume":"78","author":"Du","year":"2020","journal-title":"Int Immunopharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/nm.4332","article-title":"Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation","volume":"23","author":"Toussaint","year":"2017","journal-title":"Nat Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"218","DOI":"10.14348\/molcells.2018.0162","article-title":"Knockdown of lncRNA PVT1 inhibits vascular smooth muscle cell apoptosis and extracellular matrix disruption in a murine abdominal aortic aneurysm model","volume":"42","author":"Zhang","year":"2019","journal-title":"Mol Cells."},{"key":"B30","doi-asserted-by":"publisher","first-page":"600","DOI":"10.3109\/10799893.2015.1030412","article-title":"Signaling pathway of MAPK\/ERK in cell proliferation, differentiation, migration, senescence and apoptosis","volume":"35","author":"Sun","year":"2015","journal-title":"J Recept Signal Transduct Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"H1168","DOI":"10.1152\/ajpheart.00296.2017","article-title":"Role of myeloperoxidase in abdominal aortic aneurysm formation: mitigation by taurine","volume":"313","author":"Kim","year":"2017","journal-title":"Am J Physiol Heart Circ Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1161\/CIRCRESAHA.116.309692","article-title":"Neutrophil extracellular traps in atherosclerosis and atherothrombosis","volume":"120","author":"Doring","year":"2017","journal-title":"Circ Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"93S","DOI":"10.1016\/j.jvs.2018.05.253","article-title":"Resolvin D1 decreases abdominal aortic aneurysm formation by inhibiting NETosis in a mouse model","volume":"68","author":"Spinosa","year":"2018","journal-title":"J Vasc Surg."},{"key":"B34","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1161\/HYPERTENSIONAHA.117.09822","article-title":"Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) is required for angiotensin II\/beta-aminopropionitrile-induced abdominal aortic aneurysm","volume":"70","author":"Kawai","year":"2017","journal-title":"Hypertension."},{"key":"B35","doi-asserted-by":"publisher","first-page":"8087","DOI":"10.26355\/eurrev_202008_22493","article-title":"Up-regulation of exosomal miR-106a may play a significant role in abdominal aortic aneurysm by inducing vascular smooth muscle cell apoptosis and targeting TIMP-2, an inhibitor of metallopeptidases that suppresses extracellular matrix degradation","volume":"24","author":"Han","year":"2020","journal-title":"Eur Rev Med Pharmacol Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"7250","DOI":"10.3390\/ijms21197250","article-title":"Risk factors and mouse models of abdominal aortic aneurysm rupture","volume":"21","author":"Krishna","year":"2020","journal-title":"Int J Mol Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/bs.pmbts.2017.02.002","article-title":"The role matrix metalloproteinases in the production of aortic aneurysm","volume":"147","author":"Rabkin","year":"2017","journal-title":"Prog Mol Biol Transl Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"118","DOI":"10.3390\/ph12030118","article-title":"Matrix metalloproteinase in abdominal aortic aneurysm and aortic dissection","volume":"12","author":"Maguire","year":"2019","journal-title":"Pharmaceuticals (Basel)."},{"key":"B39","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1161\/CIRCRESAHA.114.303312","article-title":"Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis","volume":"114","author":"Knight","year":"2017","journal-title":"Circ Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.trsl.2021.02.003","article-title":"Histone citrullination as a novel biomarker and target to inhibit progression of abdominal aortic aneurysms","volume":"233","author":"Eilenberg","year":"2021","journal-title":"Transl Res"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.676612\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T04:51:04Z","timestamp":1627620664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.676612\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,30]]},"references-count":40,"alternative-id":["10.3389\/fcvm.2021.676612"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.676612","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,30]]},"article-number":"676612"}}