Potent Inhibiting Effect of Activated vitamine D3 on Aortic Aneurysm Dilatation

• Project/Area Number: 17K10753
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: Nagoya University
• Principal Investigator: NIIMI Kiyoaki 名古屋大学, 医学部附属病院, 助教 (50467312)
• Co-Investigator(Kenkyū-buntansha): 古森 公浩 名古屋大学, 医学系研究科, 教授 (40225587) ; 坂野 比呂志 名古屋大学, 医学部附属病院, 講師 (80584721) ; 杉本 昌之 名古屋大学, 医学部附属病院, 病院講師 (00447814)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥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)
• Keywords: 腹部大動脈瘤 / 活性型ビタミンD / ビタミンD / アディポサイトカイン / アディポネクチン動脈硬化 / 炎症メディエーター / モンテルカスト / M2マクロファージ / 動脈硬化 / 活性型ビタミンD3 / アディポネクチン / 炎症性メディエーター / 外科 / 生理学 / 薬理学

Outline of Final Research Achievements

The activity of endogenous MCP-1 was significantly lower in the calsitriol group than in the Saline group. However, there was no significant difference in expression level of IL-1βand MMP-9 causing degeneration of the extracellular matrix between the Saline and calsitriol groups. In that series, we decided to evaluate another anti-inflammatory subject that can suppress atherosclerotic disease. Montelukast is a selective CVS-LT-1receptor antagonist that could surpress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensinⅡ-infused apolipoprotein E-deficient AAA mouse model. Relative to control,montelukast significantly suppressed gene expression of MMP-2, MMP-9, and IL-1β.In vivo,montelukast significantly decreased aortic expansion and induced infiltration of M2 macrophages.

Academic Significance and Societal Importance of the Research Achievements

今回当初目的としたcalsitriolが大動脈瘤の原因となる炎症メディエータの抑制効果を示せなかったが、研究の過程で腹部大動脈瘤モデルマウスの確立(イソフルレンにて麻酔したマウスの皮下に浸透圧ポンプを植え込み、アンギオテンシンⅡを1000ng/kg/minの容量で28日間投与)、さらに喘息治療薬であるロイコトリエン拮抗薬のモンテルカストで大動脈瘤抑制効果をマウスで確認できたことは今後の動脈瘤治療への1つの方向性を示すことができ、またマウスの動脈瘤モデル作製に精通したことより、今後の研究に生かせる意義がある。

Research Products

• [Journal Article] Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation. (2019)
  • Author(s): Kawai Y, Narita Y, Yamawaki-Ogata A, Usui A, Komori K
  • Journal Title: Biomed Res Int. Volume: - Pages: 1-11
  • DOI: 10.1155/2019/9104680
  • Peer Reviewed
• [Journal Article] Proximal bare stent may reduce bird-beak configuration, which is associated with distal migration of stent graft in the aortic arch. (2019)
  • Author(s): Banno H, Akita N, Fujii T, Tsuruoka T, Takahashi N, Sugimoto M, Niimi K, Komori K
  • Journal Title: Ann Vasc Surg Volume: 56 Pages: 108-113
  • DOI: 10.1016/j.avsg.2018.08.081
  • Peer Reviewed
• [Journal Article] Zilver PTX Post-market Surveillance Study of Paclitaxel-Eluting Stents for Treating Femoropopliteal Artery Disease in Japan: 2-Year Results. (2019)
  • Author(s): Kichikawa K, Ichihashi S, Yokoi H, Ohki T, Nakamura M, Komori K, Nanto S, O'Leary EE, Lottes AE, Snyder SA, Dake MD
  • Journal Title: Cardiovasc Intervent Radiol. Volume: 42(3) Issue: 3 Pages: 358-364
  • DOI: 10.1007/s00270-018-2110-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Associations of nutritional status and muscle size with mortality after open aortic aneurysm repair. (2019)
  • Author(s): Kodama A, Takahashi N, Sugimoto M, Niimi K, Banno H, Komori K
  • Journal Title: J Vasc Surg Volume: 70(5) Issue: 5 Pages: 1585-1593
  • DOI: 10.1016/j.jvs.2019.01.049
  • Peer Reviewed
• [Journal Article] Direct oral anticoagulant導入後の深部静脈血栓症例の検討 (2018)
  • Author(s): 新美清章、小山明男、川井陽平、秋田直宏、藤井孝之,榊原昌志、鶴岡琢也、高橋範子、杉本昌之、児玉章朗、坂野比呂志,古森公浩
  • Journal Title: Jpn J Phlebol Volume: 29（1） Pages: 13-19
• [Journal Article] Long-term fate of renal function after open surgery for juxtarenal and pararenal aortic aneurysm (2018)
  • Author(s): Sugimoto M, Takahashi N, Niimi K, Kodama A, Banno H, Komori K
  • Journal Title: J Vasc Surg. Volume: 67(4) Issue: 4 Pages: 1042-1050
  • DOI: 10.1016/j.jvs.2017.07.121
  • Peer Reviewed / Open Access
• [Journal Article] Anatomical Suitability of the GORE EXCLUDER Iliac Branch Endoprosthesis in Japanese Patients with Common Iliac Aneurysms Treated by Standard EXCLUDER Endografts (2018)
  • Author(s): Sugimoto M, Takahashi N, Niimi K, Kodama A, Banno H, Komori K
  • Journal Title: Ann Vasc Surg. Volume: 50 Pages: 179-185
  • DOI: 10.1016/j.avsg.2017.11.071
  • Peer Reviewed / Open Access
• [Journal Article] Self-efficacy is an independent predictor for postoperative six-minute walk distance after elective open repair of abdominal aortic aneurysm. (2017)
  • Author(s): Hayashi K, Kobayashi K, Shimizu M, Tsuchikawa Y, Kodama A, Komori K, Nishida Y
  • Journal Title: Disability and Rehabilitation Volume: 40(10) Issue: 10 Pages: 1114-1118
  • DOI: 10.1080/09638288.2017.1287962
  • NAID: 120006477480
  • Peer Reviewed / Open Access
• [Journal Article] Influence of False Lumen Status on the Prognosis of Acute Type A Aortic Dissection without Urgent Surgical Treatment (2017)
  • Author(s): Tanaka A, Ishii H, Suzuki S, Ota T, Oshima H, Usui A, Komori K, Murohara T
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 2 Pages: 169-175
  • DOI: 10.5551/jat.35675
  • NAID: 130005316475
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed
• [Journal Article] Long-term Comparison of Endovascular and Open Repair of Abdominal Aortic Aneurysms: Retrospective Analysis of Matched Cohorts with Propensity Score. (2017)
  • Author(s): Sugimoto M, Koyama A, Niimi K, Kodama A, Banno H, Komori K
  • Journal Title: Annals of Vascular Surgery Volume: 43 Pages: 96-103
  • DOI: 10.1016/j.avsg.2017.01.011
  • Peer Reviewed
• [Journal Article] Outcomes of Endovascular Repair for Abdominal Aortic Aneurysms: A Nationwide Survey in Japan. (2017)
  • Author(s): Hoshina K, Ishimaru S, Sasabuchi Y, Yasunaga H, Komori K
  • Journal Title: Annals of Surgery Volume: Epub ahead of print Issue: 3 Pages: 564-573
  • DOI: 10.1097/sla.0000000000002508
  • Peer Reviewed
• [Presentation] New trial program for educating young vascular surgeons in Japan (2019)
  • Author(s): Komori K
  • Organizer: 13th China Southern Endovascular Congress
  • Int'l Joint Research
• [Presentation] Long-Term Renal Function following Endovascular and open Abdominal Aneurysm Repair (2019)
  • Author(s): Komori K
  • Organizer: 13th China Southern Endovascular Congress
  • Int'l Joint Research
• [Presentation] Diffremce between early and late apontaneouse SAC shrinkage after EVAR (2019)
  • Author(s): Sugimoto M, Takahashi N, Niimi K, Kodama A, Banno H, Komori K
  • Organizer: 33rd Annual Meeting of the European Society for Vascular Surgery
  • Int'l Joint Research
• [Presentation] Impact of the left renal vein division on tatal and split renal function after open of PARA- and Juxtarenal aortic aneurysm (2019)
  • Author(s): Sugimoto M, Takahashi N, Niimi K, Kodama A, Banno H, Komori K
  • Organizer: 33rd Annual Meeting of the European Society for Vascular Surgery
  • Int'l Joint Research
• [Presentation] outcomes of celiac artery coverage during thoracic endovascular aortic repair (2019)
  • Author(s): Banno H, Ikeda S, Kawai Y, Meshii K, Takahashi N, Sugimoto M, Niimi K, Kodama A, Komori K
  • Organizer: 33rd Annual Meeting of the European Society for Vascular Surgery
  • Int'l Joint Research
• [Presentation] The efficacy of endovascular laser ablation alone as a treatment for varicose veins (2019)
  • Author(s): Kawai,Y Aikawa K, Komori K
  • Organizer: 33rd Annual Meeting of the European Society for Vascular Surgery
  • Int'l Joint Research
• [Presentation] Long-Term (5 Years) Effectiveness Of Zilver PTX Drug Eluting Stents (DESs) For Fempop In Stent Restenosis (ISR): From The Japanese Post Market Surveillance Study (2019)
  • Author(s): Komori K
  • Organizer: VEITH symposium Connecting The Vascular Community 46th Annual
  • Int'l Joint Research
• [Presentation] Depleted Nutritional Status And Muscle Mass Increases The Risk Of Open AAA Repair:What About With EVAR (2019)
  • Author(s): Komori K
  • Organizer: VEITH symposium Connecting The Vascular Community 46th Annual
  • Int'l Joint Research
• [Presentation] 当科における弓部大動脈瘤の治療方針とその成績 (2018)
  • Author(s): 秋田直宏、藤井孝之、川井陽平、鶴岡琢也、榊原昌志、高橋範子、杉本昌之、新美清章、徳田順之、坂野比呂志、碓氷章彦、古森公浩
  • Organizer: 第46回日本血管外科学会学術総会
• [Presentation] Direct oral antioaqulant(DOAC)導入後の深部静脈血栓症例の検討 (2018)
  • Author(s): 新美清章、川井陽平、榊原昌志、秋田直宏、藤井孝之、鶴岡琢也、高橋範子、杉本昌之、坂野比呂志、古森公浩
  • Organizer: 第46回日本血管外科学会学術総会
• [Presentation] 静脈うっ滞性潰瘍治療中に生じたスルファジアジン軟膏による接触性皮膚炎の2例 (2018)
  • Author(s): 新美清章、池田脩太、秋田直宏、藤井孝之、川井陽平、榊原昌志、鶴岡琢也、高橋範子、杉本昌之、坂野比呂志、古森公浩
  • Organizer: 第38回日本静脈学会総会
• [Presentation] Current status of the treatment for the patients with AAA in Japan nationwide surgery in Japan (2018)
  • Author(s): Komori K
  • Organizer: 14th Chinese Capital Vascular Symposium
  • Int'l Joint Research
• [Presentation] Open Surgery Is The Best Treatment For Juxtarenal And Pararenal AAAs In Good Risk Patients (2018)
  • Author(s): Komori K
  • Organizer: VEITH symposium Connecting The Vascular Community 45th Annual
  • Int'l Joint Research
• [Presentation] 他家間葉系幹細胞を用いた大動脈瘤治療の可能性 (2017)
  • Author(s): 秋田直宏、緒方藍歌、藤井孝之, 田畑光紀, 小山明男, 杉本昌之, 新美清章, 児玉章朗, 坂野比呂志,成田裕司,碓氷章彦,古森公浩
  • Organizer: 第117回日本外科学会定期学術集会
• [Remarks] 名古屋大学 血管外科
  • URL: http://www.vascsurg.jp/
• [Remarks] 名古屋大学医学部医学系研究科・医学部医学科 血管外科学（第一外科学）
  • URL: https://www.med.nagoya-u.ac.jp/hospital/departments/vascular-s/
• [Remarks] 名古屋大学医学系研究科・医学部医学科 血管外科（外科学第一）
  • URL: http://www.med.nagoya-u.ac.jp/medical_J/laboratory/clinical-med/clinical-med/surgery/vascular-surg/
• [Remarks] 名古屋大学大学院医学系研究科・医学部医学科 血管外科（第一外科）
  • URL: http://www.old.med.nagoya-u.ac.jp/medical/6391/6429/kekkangekagaku.html