{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:05:23Z","timestamp":1792789523998,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T00:00:00Z","timestamp":1610496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K19364 and 17K09567"],"award-info":[{"award-number":["15K19364 and 17K09567"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Heart Foundation Dr. Hiroshi Irisawa &amp; Dr. Aya Irisawa Memorial Research Grant","award":["none"],"award-info":[{"award-number":["none"]}]},{"DOI":"10.13039\/501100003837","name":"Ichiro Kanehara Foundation","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/501100003837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4\/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin\/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.<\/jats:p>","DOI":"10.3390\/ijms22020722","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T11:52:32Z","timestamp":1610538752000},"page":"722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Yukino","family":"Ogura","sequence":"first","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9759-1008","authenticated-orcid":false,"given":"Kazuko","family":"Tajiri","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Murakoshi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DongZhu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Yonebayashi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Okabe","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duo","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzuno","family":"Shimoda","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoughu","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixun","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2332-111X","authenticated-orcid":false,"given":"Kazutaka","family":"Aonuma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4724-3299","authenticated-orcid":false,"given":"Masaki","family":"Ieda","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/S0140-6736(18)31992-5","article-title":"NCD Countdown 2030: Worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4","volume":"392","author":"Bennett","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.jacc.2013.11.009","article-title":"ACCF\/AHA\/ASE\/ASNC\/HFSA\/HRS\/SCAI\/SCCT\/SCMR\/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease","volume":"63","author":"Wolk","year":"2014","journal-title":"J. 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