{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T15:49:50Z","timestamp":1793720990062,"version":"4.6.1"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2023,2,17]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Apoe<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      and\n                      <jats:italic>Mmp12<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      \/\n                      <jats:italic>Apoe<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH\n                      <jats:sub>1-5<\/jats:sub>\n                      (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II\u2013infused mice were determined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Unexpectedly, death from aortic rupture was significantly higher in\n                      <jats:italic>Mmp12<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      \/\n                      <jats:italic>Apoe<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in\n                      <jats:italic>\n                        Mmp12\n                        <jats:sup>-\/-<\/jats:sup>\n                      <\/jats:italic>\n                      aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in\n                      <jats:italic>Mmp12<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice pointed to complement overactivation. Treatment with IgG-FH\n                      <jats:sub>1-5<\/jats:sub>\n                      decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II\u2013infused\n                      <jats:italic>Mmp12<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II\u2013infused mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>An MMP-12 deficiency\/complement activation\/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.122.322096","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T05:00:57Z","timestamp":1674536457000},"page":"432-448","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Homeostatic, Non-Canonical Role of Macrophage Elastase in Vascular Integrity"],"prefix":"10.1161","volume":"132","author":[{"given":"Mani","family":"Salarian","sequence":"first","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0723-3662","authenticated-orcid":true,"given":"Mean","family":"Ghim","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-8075","authenticated-orcid":true,"given":"Jakub","family":"Toczek","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinah","family":"Han","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6097-6038","authenticated-orcid":true,"given":"Dar","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT (D.W., B.S., A.B.R., J.D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1076-1922","authenticated-orcid":true,"given":"Bart","family":"Spronck","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT (D.W., B.S., A.B.R., J.D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay B.","family":"Ramachandra","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT (D.W., B.S., A.B.R., J.D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Joon","family":"Jung","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunjan","family":"Kukreja","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiasheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deaneira","family":"Lakheram","sequence":"additional","affiliation":[{"name":"Alexion Pharmaceuticals, New Haven, CT (D.L., S.-K.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Kwon","family":"Kim","sequence":"additional","affiliation":[{"name":"Alexion Pharmaceuticals, New Haven, CT (D.L., S.-K.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1011-2025","authenticated-orcid":true,"given":"Jay D.","family":"Humphrey","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT (D.W., B.S., A.B.R., J.D.H.)."},{"name":"Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5074-3510","authenticated-orcid":true,"given":"Mehran M.","family":"Sadeghi","sequence":"additional","affiliation":[{"name":"Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."},{"name":"VA Connecticut Healthcare System, West Haven, CT (M.S., M.G., J.T., J.H., J.-J.J., G.K., J.Z., M.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/16.suppl_k.4"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-742676"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1602532"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.027646"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.312413"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci2182"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2009.80"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci8931"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2004.12.004"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci38136"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-12-129080"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08181"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3508"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.10.015"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.03.054"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.110.219147"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep38345"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci7818"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.97918"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2016.07.105"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.9.3942"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10138"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20182151"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im1401s83"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1115\/1.1824130"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-013-0799-1"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmbbm.2020.104264"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.55106"},{"key":"e_1_3_3_31_2","first-page":"9","article-title":"The murine angiotensin ii-induced abdominal aortic aneurysm model: rupture risk and inflammatory progression patterns.","volume":"1","author":"Cao RY","year":"2010","unstructured":"Cao, RY, Amand, T, Ford, MD, Piomelli, U, Funk, CD. The murine angiotensin ii-induced abdominal aortic aneurysm model: rupture risk and inflammatory progression patterns. Front Pharmacol. 2010;1:9. Doi: 10.3389\/fphar.2010.00009","journal-title":"Front Pharmacol"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0114-9"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302937"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-019-0286-3"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-018-0024-0"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.612402"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2020.09.028"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.118.313187"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2021.0336"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.114.305115"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.cj-17-0229"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci0215334"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2008.167"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2007.12.001"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.09.006"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04717-4"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00262"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2020.02.006"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2019.06.016"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119000109"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.105"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.116.307786"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.117.309897"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.05.014"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.041460"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2017.05.010"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.1883"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2004.02.030"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.1.89"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01618"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3321"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.93.9.1716"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3320"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12034"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124615"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0175-2"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m600222200"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01186"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.122.322096","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T00:57:46Z","timestamp":1715561866000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.122.322096"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,17]]},"references-count":68,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,2,17]]}},"alternative-id":["10.1161\/CIRCRESAHA.122.322096"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.122.322096","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,17]]},"assertion":[{"value":"2022-10-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}