{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:22:05Z","timestamp":1793164925407,"version":"4.5.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Abdominal aortic aneurysm (AAA) is an arterial disease characterized by dilatation of the aortic wall. It has been suggested that neutrophil counts and neutrophil elastase activity are associated with AAA. We investigated whether a neutrophil elastase (NE) inhibitor, sivelestat (Siv), had a protective effect against angiotensin II (AngII)-induced AAAs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Male apolipoprotein E-deficient mice were assigned into three groups: Vehicle\u2005+\u2005saline, AngII\u2005+\u2005saline, and AngII\u2005+\u2005Siv. All mice were administered intraperitoneally with either Siv or vehicle twice daily after AngII infusion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>In the 4-week AngII infusion study, plasma NE concentration (P\u2005=\u20050.041) and its activity (P\u2005=\u20050.011) were elevated by AngII. These increases were attenuated by Siv (concentration:P\u2005=\u20050.010, activity:P\u2005=\u20050.027). Further, plasma elastase activity was closely correlated with aortic width (R\u2005=\u20050.6976, P\u2005&amp;lt;\u20050.001). In the 1-week AngII infusion study, plasma and tissue elastase activity increased by AngII (plasma:P\u2005=\u20050.034, tissue:P\u2005&amp;lt;\u20050.001), but were reduced by Siv (plasma:P\u2005=\u20050.014, tissue:P\u2005=\u20050.024). AngII increased aortic width (P\u2005=\u20050.011) but was attenuated by co-administration of Siv (P\u2005=\u20050.022). Moreover, Siv decreased the incidence of AAAs (P\u2005=\u20050.009). Elastin fragmentation induced by AngII was reduced by Siv. Many inflammatory cells that were either CD68 or Gr-1 positive were observed in the AngII\u2005+\u2005saline group, whereas few inflammatory cells were accumulated in the AngII\u2005+\u2005Siv group. MMP-2 and MMP-9 were enhanced by AngII, but were reduced by Siv. In vitro, MMP-2 activity was induced by human NE (medium:P\u2005&amp;lt;\u20050.001, cells:P\u2005=\u20050.001), which was attenuated by co-incubation of Siv in medium (P\u2005&amp;lt;\u20050.001) and protein of human aortic smooth muscle cells (P\u2005=\u20050.001).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Siv attenuated AngII-induced AAA through the inhibition of NE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ajh\/hpad107","type":"journal-article","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T17:21:28Z","timestamp":1699464088000},"page":"349-357","source":"Crossref","is-referenced-by-count":6,"title":["Neutrophil Elastase Inhibition by Sivelestat (ONO-5046) Attenuates AngII-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice"],"prefix":"10.1093","volume":"37","author":[{"given":"Yoshiko","family":"Hada","sequence":"first","affiliation":[{"name":"Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Science , Okayama ,","place":["Japan"]},{"name":"Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Science , Okayama ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7629-7678","authenticated-orcid":false,"given":"Haruhito A","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Science , Okayama ,","place":["Japan"]},{"name":"Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Science , Okayama ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shugo","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Science , Okayama ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nozomu","family":"Otaka","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Science , Okayama ,","place":["Japan"]},{"name":"Department of Nephrology and Rheumatology, Kagawa Prefectural Central Hospital , Kagawa ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyoshi","family":"Katayama","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Science , Okayama ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkateswaran","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Missouri , Columbia, Missouri ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Daugherty","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center, University of Kentucky , Lexington, Kentucky ,","place":["USA"]},{"name":"Department of Physiology, University of Kentucky , Lexington, Kentucky ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of 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