| Project/Area Number |
17K09567
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Cardiovascular medicine
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| Research Institution | University of Tsukuba (2018-2019)
National Institutes of Biomedical Innovation, Health and Nutrition (2017) |
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Principal Investigator |
Tajiri Kazuko 筑波大学, 医学医療系, 助教 (60633914)
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| Co-Investigator(Kenkyū-buntansha) |
酒井 俊 筑波大学, 医学医療系, 講師 (30282362)
佐藤 明 筑波大学, 医学医療系, 准教授 (30528469)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 心筋梗塞 / 好中球エラスターゼ / 好中球細胞外トラップ / 心筋リモデリング / 好中球細胞トラップ |
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| Outline of Final Research Achievements |
Neutrophils form extracellular traps (NETs) by releasing decondensed chromatin decorated with granule proteins including neutrophil elastase (NE). However, the pathological role of NETs in myocardial infarction (MI) remains unknown. Here we show that the neutrophils form NETs in the myocardium after MI, which reveal significant NE proteolytic activity. When subjected to permanent coronary artery ligation, wild-type (WT) mice produced large quantities of NETs. In MI mice, gene expression of Annexin A1 (AnxA1), an anti-inflammatory and proresolving mediator, was upregulated, however, most AnxA1 protein was degraded accompanied with high elastase activity in the myocardium. Both NE deficiency and NE inhibitor sivelstat inhibited NETs formation and accelerated resolution of acute inflammation associated with increased amount of intact AnxA1 and improved survival and cardiac function after MI. Inhibiting NETosis may improve healing and reduce NET-driven excessive inflammation after MI.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、嚢胞性線維症に対して遺伝子組換えヒトDNA分解酵素製剤が使用され、有効性を示している。嚢胞性線維症も、その病態にNETsが関与していることが明らかになっているが（Nat Med 2010）、DNA分解酵素はNETsの主成分であるDNAを分解し、NETs形成を阻害するため嚢胞性線維症に対して有効である可能性が示唆されている。本研究で、心筋梗塞におけるNETs形成阻害による抗炎症効果、ならびにその後のリモデリング抑制効果を示したため、DNA分解酵素製剤を含むNETs抑制薬が新たな治療法になる可能性が期待できる。
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