Exploratory study of novel diagnostic and therapeutic methods targeting macrophages for aortic aneurysms

• Project/Area Number: 17K09593
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kagoshima University
• Principal Investigator: Miyata Masaaki 鹿児島大学, 医歯学域医学系, 教授 (00347113)
• Co-Investigator(Kenkyū-buntansha): 池田 義之 鹿児島大学, 医歯学域医学系, 准教授 (00573023) ; 赤崎 雄一 鹿児島大学, 医歯学域鹿児島大学病院, 助教 (00631920) ; 大石 充 鹿児島大学, 医歯学域医学系, 教授 (50335345)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 大動脈瘤 / マクロファージ / 葉酸レセプターβ / 活性化マクロファージ / レジストリー

Outline of Final Research Achievements

The role of macrophages in the pathogenesis of aortic aneurysms was investigated. In a mouse model of aortic aneurysm, we found that deletion of all macrophages suppressed the onset and progression of aortic aneurysm and promoted aortic aneurysm regression. Furthermore, in a mouse model of aneurysm, deletion of only activated macrophages suppressed the onset of aortic aneurysm and promoted regression of aortic aneurysm. In addition, immunohistochemistry using folate receptor β (FRβ) monoclonal antibody confirmed the presence of activated macrophages expressing FRβ in the removed aorta of patients undergoing aortic aneurysm surgery. A Kagoshima aortic aneurysm patient registry was established and blood soluble FRβ levels were measured in these patients.

Academic Significance and Societal Importance of the Research Achievements

本研究において、全マクロファージや活性化マクロファージが大動脈瘤の発症、進展、抑制に関与することが明らかになった。さらに、抗FRβモノクローナル抗体に緑膿菌毒素を結合させたFRβイムノトキシンにて活性化マクロファージを抑制することで、大動脈瘤モデルマウスの大動脈瘤の発症を抑制し、大動脈瘤を退縮させたことより、FRβイムノトキシンや抗FRβ抗体薬による活性化マクロファージを標的する大動脈瘤の新規治療法の開発にも繋がる臨床的価値の高い研究結果である。

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Journal Article] Importance of NLRP3 Inflammasome in Abdominal Aortic Aneurysms (2021)
  • Author(s): Shi J, Guo J, Li Z, Xu B, Miyata M
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 5 Pages: 454-466
  • DOI: 10.5551/jat.RV17048
  • NAID: 130008033031
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-05-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] No Effect of Hypercholesterolemia on Elastase-Induced Experimental Abdominal Aortic Aneurysm Progression (2021)
  • Author(s): Ikezoe Toru、Shoji Takahiro、Guo Jia、Shen Fanru、Lu Hong S.、Daugherty Alan、Nunokawa Masao、Kubota Hiroshi、Miyata Masaaki、Xu Baohui、Dalman Ronald L.
  • Journal Title: Biomolecules Volume: 11 Issue: 10 Pages: 1434-1434
  • DOI: 10.3390/biom11101434
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 動脈硬化 (2021)
  • Author(s): 池田義之, 宮田昌明, 大石 充
  • Journal Title: 臨牀と研究 Volume: 98 Pages: 768-770
• [Journal Article] Association of risk factors for atherosclerosis, including high-sensitivity C-reactive protein, with carotid intima-media thickness, plaque score, and pulse wave velocity in a male population (2020)
  • Author(s): Ojima S, Kubozono T, Kawasoe S, Kawabata T, Miyata M, Miyahara H, Maenohara S, Ohishi M
  • Journal Title: Hypertens Res Volume: 43 Issue: 5 Pages: 422-430
  • DOI: 10.1038/s41440-019-0388-2
  • Peer Reviewed
• [Journal Article] Correlation of Right Ventricular Wall Stress With Plasma B-Type Natriuretic Peptide Levels in Patients With Pulmonary Hypertension (2019)
  • Author(s): Uchiyama N, Yuasa T, Miyata M, Horizoe Y, Chaen H, Kubota K, Takasaki K, Mizukami N, Kisanuki A, Ohishi M
  • Journal Title: Circulation Journal Volume: 83 Issue: 6 Pages: 1278-1285
  • DOI: 10.1253/circj.CJ-18-1155
  • NAID: 130007652738
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-05-24
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of Biphasic Right Ventricular Outflow Doppler Waveform in Patients with Pulmonary Hypertension (2019)
  • Author(s): Horizoe Y, Takasaki K, Miyata M, Chaen H, Kubota K, Mizukami N, Yuasa T, Kisanuki A, Ohishi M
  • Journal Title: International Heart Journal Volume: 60 Issue: 1 Pages: 108-114
  • DOI: 10.1536/ihj.18-149
  • NAID: 130007557178
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-01-31
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of VEGF (Vascular Endothelial Growth Factor)-A or its Receptor Activity Suppresses Experimental Aneurysm Progression in the Aortic Elastase Infusion Model (2019)
  • Author(s): Xu B, Iida Y, Glover KJ, Ge Y, Wang Y, Xuan H, Hu X, Tanaka H, Wang W, Fujimura N, Miyata M, Shoji T, Guo J, Zheng X, Gerritsen M, Kuo C, Michie SA, Dalman RL
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 39 Issue: 8 Pages: 1652-1666
  • DOI: 10.1161/atvbaha.119.312497
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Propagermanium, a CCR2 inhibitor, attenuates cerebral ischemia/reperfusion injury through inhibiting inflammatory response induced by microglia (2019)
  • Author(s): He S, Liu R, Li B, Huang L, Fan W, Tembachako CR, Zheng X, Xiong X, Miyata M, Xu B, Li Y, Fang W
  • Journal Title: Neurochem Int. 2019;125:99-110 Volume: 125 Pages: 99-110
  • DOI: 10.1016/j.neuint.2019.02.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dynamics of Soluble Thrombomodulin and Circulating miRNAs in Patients with Atrial Fibrillation Undergoing Radiofrequency Catheter Ablation (2019)
  • Author(s): Namino F, Yamakuchi M, Iriki Y, Okui H, Ichiki H, Maenosono R, Oketani N, Masamoto I, Miyata M, Horiuchi M, Hashiguchi T, Ohishi M, Maruyama I
  • Journal Title: Clin Appl Thromb Hemost Volume: 25 Pages: 107602961985157-107602961985157
  • DOI: 10.1177/1076029619851570
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of exercise-induced pulmonary hypertension in patients with connective tissue disease (2019)
  • Author(s): Miyanaga S, Kubota K, Iwatani N, Higo K, Miyata M, Horizoe Y, Ojima S, Kawasoe S, Kubozono T, Ohishi M
  • Journal Title: Heart Vessels Volume: 34 Issue: 9 Pages: 1509-1518
  • DOI: 10.1007/s00380-019-01373-6
  • Peer Reviewed / Open Access
• [Journal Article] Uric Acid Level and New-Onset Atrial Fibrillation in the Japanese General Population ― Longitudinal Study ― (2018)
  • Author(s): Kawasoe S, Kubozono T, Yoshifuku S, Ojima S, Miyata M, Miyahara H, Maenohara S, Ohishi M
  • Journal Title: Circulation Journal Volume: 83 Issue: 1 Pages: 156-163
  • DOI: 10.1253/circj.CJ-18-0508
  • NAID: 130007550394
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-12-25
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenic and therapeutic significance of angiotensin II type I receptor in abdominal aortic aneurysms (2018)
  • Author(s): Xu B, Xuan H, Iida Y, Miyata M, Dalman RL.
  • Journal Title: Curr Drug Targets Volume: 印刷中 Issue: 11 Pages: 1318-1326
  • DOI: 10.2174/1389450119666180122155642
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CCR2-dependent monocytes/macrophages exacerbate acute brain injury but promote functional recovery after ischemic stroke in mice (2018)
  • Author(s): Fang W, Zhai X, Han D, Xiong X, Wang T, Zeng X, He S, Liu R, Miyata M, Xu B, Zhao H
  • Journal Title: Theranostics Volume: 8 Issue: 13 Pages: 3530-3543
  • DOI: 10.7150/thno.24475
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition or deletion of angiotensin II type 1 receptor suppresses elastase-induced experimental abdominal aortic aneurysms (2017)
  • Author(s): Xuan H, Xu B, Wang W, Tanaka H, Fujimura N, Miyata M, Michie SA, Dalman RL
  • Journal Title: J Vasc Surg Volume: 印刷中 Issue: 2 Pages: 573-584
  • DOI: 10.1016/j.jvs.2016.12.110
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neurohumoral Modulation During Waon Therapy in Chronic Heart Failure ― Subanalysis of Waon-CHF Study ― (2017)
  • Author(s): Ichiki T, Burnett JC Jr, Scott CG, Heublein DM, Miyata M, Kinugawa K, Inoue T, Tei C, WAON-CHF Study Investigators.
  • Journal Title: Circulation Journal Volume: 81 Issue: 5 Pages: 709-716
  • DOI: 10.1253/circj.CJ-16-1117
  • NAID: 130005612069
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes (2017)
  • Author(s): Kawasoe S, Maruguchi Y, Kajiya S, Uenomachi H, Miyata M, Kawasoe M, Kubozono T, Ohishi M
  • Journal Title: BMC Pharmacol Toxicol Volume: 18 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s40360-017-0125-x
  • Peer Reviewed / Open Access
• [Journal Article] High Pulse Wave Velocity Has a Strong Impact on Early Carotid Atherosclerosis in a Japanese General Male Population (2017)
  • Author(s): Takuro Kubozono, Masaaki Miyata, Shin Kawasoe, Satoko Ojima, Shiro Yoshifuku, Hironori Miyahara, Shigeho Maenohara, Mitsuru Ohishi
  • Journal Title: Circulation Journal Volume: 81 Issue: 3 Pages: 310-315
  • DOI: 10.1253/circj.CJ-16-0687
  • NAID: 130005242976
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Presentation] Clinical impact of non-HDL-C assessment to predict occurrence of new lesions after percutaneous coronary intervention in stable angina patients prescribed statins (2021)
  • Author(s): Kanda D, Miyata M, Anzaki K, Arikawa R, Sonoda T, Ohmure K, Tokushige A, Ikeda Y, Ohishi M
  • Organizer: 70th Annual Scientific Session of the American College of Cardiology
  • Int'l Joint Research
• [Presentation] Priority of non-HDL-C assessment to predict occurrence of new lesions after percutaneous coronary intervention in stable angina patients with diabetes mellitus prescribed strong statins (2021)
  • Author(s): Kanda D, Miyata M, Anzaki K, Arikawa R, Sonoda T, Ohmure K, Tokushige A, Ikeda Y, Ohishi M
  • Organizer: ESC Congress 2021
  • Int'l Joint Research
• [Presentation] Atherosclerotic risk factors associated with carotid plaque progression are different depending on the severity of plaque stage: a longitudinal study in general population (2021)
  • Author(s): Ojima S, Kubozono T, Kawasoe S, Kawsabata T, Salim Anwar A, Miyahara H, Tokushige K, Miyata M, Ikeda Y, Ohishi M
  • Organizer: American Heart Association’s annual Scientific Sessions 2021
  • Int'l Joint Research
• [Presentation] 末梢血管と和温療法 (2021)
  • Author(s): 宮田昌明
  • Organizer: 第27回 日本心臓リハビリテーション学会学術集会
• [Presentation] How to reduce the dose of contrast during implanting leadless pacemaker (2021)
  • Author(s): Fukuyado M, Oketani N, Tagata T, Yokomine T, Ohmure K, Imamura S, Kawasoe M, Otsuji H, Chaen H, Ogawa M, Miyata M
  • Organizer: 第67回 日本不整脈心電学会学術大会
• [Presentation] リスク重複の概念とリスクアセスメント (2020)
  • Author(s): 宮田昌明
  • Organizer: 第52回 日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] Atrial fibrillation termination caused by electrogram based ablation; compared with CFAE v.s. CFAE+dispersion (2020)
  • Author(s): Yoshimoto I, Oketani N, Tagata K, Yokomine T, Nomoto Y, Omure K, Chaen H, Kawazoe M, Ogawa M, Miyata M, Ohishi. M
  • Organizer: 第84回 日本循環器学会学術集会
• [Presentation] Transition of red cell distribution width before and after catheter ablation for atrial fibrillation is an independent predictor for recurrence (2020)
  • Author(s): Yoshimoto I, Inoue K, Kitagaki R, Okada M, Tanaka N, Toyoshima Y, Oka T, Tanaka K, Okamura A, Iwakura K, Fujii K, Oketani N, Ichiki H, Miyata M, Ohishi M
  • Organizer: 第84回 日本循環器学会学術集会
• [Presentation] Comparison of prognostic predictors after return of spontaneous circulation between cardiac and non-cardiac cardiopulmonary arrest (2019)
  • Author(s): Ohmure K, Miyata M, Tagata K, Yokomine T, Nomoto Y, Imamura S, Kawasoe M, Chaen H, Oketani N, Ogawa M, Ohishi M
  • Organizer: American Heart Association Resuscitation Science Symposium 2019
  • Int'l Joint Research
• [Presentation] Percutaneous extraction for misplacement of permanent pacemaker leads within the left main coronary artery and left ventricle (2019)
  • Author(s): Yoshimoto I, Oketani N, Ogawa M, Kamata R, Nomoto Y, Imamura S, Oomure K, Chaen H, Miyata M, Hamasaki S, Ohishi M.
  • Organizer: European Society of Cardiology (ESC) Congress 2019
  • Int'l Joint Research
• [Presentation] 高齢心不全患者に対する和温療法の効果 (2019)
  • Author(s): 宮田昌明
  • Organizer: 第84回 日本温泉気候物理医学会総会・学術集会
  • Invited
• [Presentation] Atrioventricular nodal ablation combined with leadless pacemaker (2019)
  • Author(s): Fukuyado M, Oketani N, Yoshimoto I, Miyata M, Ohishi M
  • Organizer: 第66回 日本不整脈心電学会学術集会
• [Presentation] Stent implantation for left main trunk after percutaneous extraction of permanent pacemaker lead accidentally implanted into the left main trunk (2019)
  • Author(s): Ogawa M, Oketani N, Chaen H, Imamura S, Ohmure K, Nomoto Y, Yokomine Y, Tagata T, Kawasoe M, Miyata M, Ohishi M
  • Organizer: 第28回日本心血管インターベンション治療学会 CVIT 2019
• [Presentation] Prognostic predictors in patients with cardiopulmonary arrest: a novel formula to predict death (2019)
  • Author(s): Imamura S, Miyata M, Kamata R, Nomoto Y, Yoshimoto I, Ohmure K, Chaen H, Oketani N, Ogawa M, Hamasaki H, Yoshihara H, Ohishi M
  • Organizer: 第83回日本循環器学会総会・学術集会
• [Presentation] The Patients with Rheumatoid Arthritis Had a Risk of Progression on Aortic Valve Stenosis (2019)
  • Author(s): Ojima S, Kubozono T, Kawasoe S, Ohtsubo H, Miyata M, Ohishi M
  • Organizer: 第83回日本循環器学会総会・学術集会
• [Presentation] Incidence of Asymptomatic Stroke or Hemopericardium in Catheter Ablation for Atrial Fibrillation with Uninterrupted Use of Edoxaban, Rivaroxaban, or Warfarin (2019)
  • Author(s): Yoshimoto I, Oketani N, Iriki Y, Okui H, Ichiki H, Maenosono R, Namino F, Miyata M, Ohishi M
  • Organizer: 第83回日本循環器学会総会・学術集会
• [Presentation] 温泉気候物理医学を科学する (2018)
  • Author(s): 宮田昌明
  • Organizer: 第83回 日本温泉気候物理医学会 総会・学術集会
  • Invited
• [Presentation] 和温療法を心臓リハビリに活かす (2018)
  • Author(s): 宮田昌明
  • Organizer: 第24回 日本心臓リハビリテーション学会学術集会
  • Invited
• [Presentation] Impaired endothelial function is associated with neointimal abnormalities after drug-eluting stents deployment assessed by optical coherence tomography in patients with ischemic heart disease (2018)
  • Author(s): Uchikado Y, Yoshino S, Miyata M, Anzaki K, Ohmure K, Tabata H, Tateishi S, Ohishi M
  • Organizer: European Society of Cardiology (ESC) Congress 2018
  • Int'l Joint Research
• [Presentation] Pupil diameter predicts the outcome in patients with cardiopulmonary arrest (2018)
  • Author(s): Imamura S, Miyata M, Kamata R, Nomoto Y, Yoshimoto I, Ohmure K, Chaen H, Oketani N, Ogawa M, Hamasaki H, Yoshihara H, Ohishi M
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] Rheumatoid arthritis is the risk of progression on aortic valve stenosis in elderly patients (2018)
  • Author(s): Ojima S, Kubozono T, Kawasoe S, Ohtsubo H, Miyata M, Ohishi M
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] Estrogen-induced alternative autophagy plays a crucial role in protecting artery from senescence and atherosclerosis (2017)
  • Author(s): Sasaki Y, Ikeda Y, Iwabayashi M, Akasaki Y, Higuchi K, Miyata M, Ohishi M
  • Organizer: American Heart Association 2017
  • Int'l Joint Research
• [Presentation] Renin-angiotensin signal develops arterial senescence and atherosclerosis via modulation of mitochondrial dynamics (2017)
  • Author(s): Ikeda Y, Iwabayashi M, Sasaki Y, Akasaki Y, Higuchi K, Miyata M, Ohishi M
  • Organizer: AHA Council on Hypertension 2017
  • Int'l Joint Research
• [Presentation] ミトコンドリアダイナミクスの血管老化および動脈硬化に及ぼす影響 (2017)
  • Author(s): 池田義之, 岩林正明, 佐々木雄一, 赤﨑雄一, 宮田昌明, 大石 充
  • Organizer: 第49回 日本動脈硬化学会総会・学術集会
• [Remarks] 鹿児島大学研究者総覧 宮田 昌明
  • URL: http://ris.kuas.kagoshima-u.ac.jp/html/100004926_ja.html?k=%E5%AE%AE%E7%94%B0%E3%80%80%E6%98%8C%E6%98%8E
• [Remarks] 鹿児島大学 研究シーズ
  • URL: https://seeds.krcc.kagoshima-u.ac.jp/seeds_info/pdf/35-Ls-miyata-med.pdf
• [Remarks] 鹿児島大学 研究者総覧 宮田 昌明
  • URL: http://ris.kuas.kagoshima-u.ac.jp/html/100004926_ja.html?k=%E5%AE%AE%E7%94%B0%E3%80%80%E6%98%8C%E6%98%8E
• [Remarks] 鹿児島大学医学部保健学科 看護学専攻 教員紹介
  • URL: https://www.kufm.kagoshima-u.ac.jp/~health/nursing/staff/field04.html
• [Remarks] 鹿児島大学産学官連携推進センター 活性化マクロファージを標的とした動脈硬化の新規診断・治療法の開発
  • URL: http://www.rdc.kagoshima-u.ac.jp/seeds_search/upload/16-Ls-miyata-med.pdf
• [Remarks] 鹿児島大学研究者総覧、宮田昌明
  • URL: http://ris.kuas.kagoshima-u.ac.jp/html/100004926_ja.html?k=%E5%AE%AE%E7%94%B0%E6%98%8C%E6%98%8E
• [Remarks] 鹿児島大学大学院 医歯学総合研究科 心臓血管・高血圧内科学 スタッフ紹介
  • URL: http://www.kufm.kagoshima-u.ac.jp/~intmed1/staff/details/miyata.html