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T-cell coinhibitory molecule cytotoxic T-lymphocyte\u2013associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)\/apolipoprotein E\u2013deficient (<jats:italic>Apoe<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice or control <jats:italic>Apoe<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4<jats:sup>+<\/jats:sup> T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c<jats:sup>+<\/jats:sup> dendritic cells in lymphoid tissues. CTLA-4-Tg\/<jats:italic>Apoe<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice had reduced accumulation of macrophages and CD4<jats:sup>+<\/jats:sup> T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.<\/jats:p>","DOI":"10.1038\/s41598-019-44523-6","type":"journal-article","created":{"date-parts":[[2019,5,30]],"date-time":"2019-05-30T10:02:41Z","timestamp":1559210561000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["CTLA-4 Protects against Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice"],"prefix":"10.1038","volume":"9","author":[{"given":"Hilman Zulkifli","family":"Amin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiji","family":"Mizoguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuo","family":"Emoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naofumi","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tokiko","family":"Tabata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayo","family":"Horibe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Kawauchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7207-4656","authenticated-orcid":false,"given":"Yoshiyuki","family":"Rikitake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-ichi","family":"Hirata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,5,30]]},"reference":[{"key":"44523_CR1","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1161\/01.ATV.0000245819.32762.cb","volume":"26","author":"J Golledge","year":"2006","unstructured":"Golledge, J., Muller, J., Daugherty, A. & Norman, P. 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