{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:16:54Z","timestamp":1790713014660,"version":"4.1.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2020,4,9]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide\u2010binding oligomerization domain\u2013like receptor pyrin domain containing 3 (NLRP3)\u2013caspase\u20101 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              In a model of sporadic aortic aneurysm and dissection induced by challenging wild\u2010type mice with a high\u2010fat, high\u2010cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge\u2010induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3\u2013caspase\u20101 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP\u20109) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase\u20101 directly activated MMP\u20109 by cleaving its N\u2010terminal inhibitory domain. Moreover, the genetic knockdown of\n              <jats:italic>Nlrp3<\/jats:italic>\n              or\n              <jats:italic>Casp\u20101<\/jats:italic>\n              in mice or treatment of mice with MCC950 diminished the challenge\u2010induced N\u2010terminal cleavage of MMP\u20109, MMP\u20109 activation, and aortic destruction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Our findings suggest that the NLRP3\u2013caspase\u20101 inflammasome directly activates MMP\u20109. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.119.014044","type":"journal-article","created":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T09:00:30Z","timestamp":1585558830000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":118,"title":["Targeting the NLRP3 Inflammasome With Inhibitor MCC950 Prevents Aortic Aneurysms and Dissections in Mice"],"prefix":"10.1161","volume":"9","author":[{"given":"Pingping","family":"Ren","sequence":"first","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Appel","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Luo","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avril A. B.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience University of Queensland Brisbane Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience University of Queensland Brisbane Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Coselli","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianna M.","family":"Milewicz","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Department of Internal Medicine The University of Texas Health Science Center at Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying H.","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"LeMaire","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX"},{"name":"Department of Cardiovascular Surgery Texas Heart Institute Houston TX"},{"name":"Cardiovascular Research Institute Baylor College of Medicine Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.08.025"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.05.029"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.11.077"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09663"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3452"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.303763"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.02.005"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.116.307648"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3806"},{"key":"e_1_3_2_11_2","first-page":"828","article-title":"The selective NLRP3\u2010inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction","volume":"38","author":"van Hout GP","year":"2017","unstructured":"van Hout GP, Bosch L, Ellenbroek GH, de Haan JJ, van Solinge WW, Cooper MA, Arslan F, de Jager SC, Robertson AA, Pasterkamp G, Hoefer IE. The selective NLRP3\u2010inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J. 2017;38:828\u2013836.","journal-title":"Eur Heart J"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309575"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-26775-w"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12248-z"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7818"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07725"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.300735"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.01.022"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.02.016"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2016.12.014"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.006347"},{"key":"e_1_3_2_22_2","first-page":"76","article-title":"Matrix metalloproteinases and cardiovascular diseases","volume":"13","author":"Papazafiropoulou A","year":"2009","unstructured":"Papazafiropoulou A, Tentolouris N. Matrix metalloproteinases and cardiovascular diseases. Hippokratia. 2009;13:76\u201382.","journal-title":"Hippokratia"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8931"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2014.03.027"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejvs.2007.12.004"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.551572"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.96.7.2228"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2013.06.007"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2125"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00624.x"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2012.86"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.119.014044","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T11:26:42Z","timestamp":1715599602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.119.014044"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,9]]},"references-count":30,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2020,4,9]]}},"alternative-id":["10.1161\/JAHA.119.014044"],"URL":"https:\/\/doi.org\/10.1161\/jaha.119.014044","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,9]]},"assertion":[{"value":"2019-07-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e014044"}}