自己由来遊離核酸断片の認識を介した動脈硬化発症機序の解明

2016 Fiscal Year Research-status Report

• Project/Area Number: 16K09517
• Research Institution: The University of Tokushima
• Principal Investigator: 福田 大受 徳島大学, 大学院医歯薬学研究部(医学系), 特任講師 (40637568)
• Co-Investigator(Kenkyū-buntansha): 佐田 政隆 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (80345214)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 動脈硬化 / 炎症 / マクロファージ

Outline of Annual Research Achievements

動脈硬化の発症には、血管における慢性炎症が重要な役割を果たしている。慢性炎症の惹起には、マクロファージの活性化が重要であるが、その機序は不明な点が多い。本研究はToll-like受容体(TLR9)とそのリガンドとなる自己由来の遊離核酸断片の役割について研究を行っている。
これまで、動脈硬化マウスであるアポリポ蛋白E(ApoE)欠損マウスとTLR9欠損マウスを交配したApoE/TLR9 dKOマウスは、通常のApoE欠損マウスと比較して、アンジオテンシンII誘導下での動脈硬化病変の進展が抑制されていることが判明した。動脈硬化病変の組織学的検索において、各種炎症性物質の発現がApoE/TLR9 dKOマウスで低下しており、TLR9の欠損によって、血管の炎症が減弱することが推測された。さらに、定量的PCRなどの各種分子生物学的手法を用いて炎症性物質の発現を検討したところ、ApoE/TLR9 dKOマウスは、ApoE欠損マウスと比較して、炎症性物質の発現が低下していることも確認できた。腹腔内マクロファージを用いた検討でも、ApoE/TLR9 dKOマウス由来のマクロファージは、ApoE KOマクロファージに比べて、TLR9アゴニストなどの刺激化における、炎症性物質の発現が低下していた。現在、骨髄移植によって作製した骨髄特異的TLR9発現/欠損ApoE欠損マウスの解析と、TLR9欠損が、動脈硬化や炎症を抑制する分子機序を検討している。
一部の結果は2016年11月に米国ボストンで開催された International Vascular Biology Meeting で発表を行った。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

当初予定していたin vivo実験が順調に経過し、現在、最終の解析段階である。分子メカニズムの解析も並行して、行うことができており、可能であれば、H29年度内に、論文化を行う予定である。

Strategy for Future Research Activity

in vivo実験とin vitro実験のまとめを行いながら、論文化に向けて不足データの収集に努める。臨床検体を用いた検討にも検討領域を広げていきたいと考えている。

Research Products

• [Journal Article] Dipeptidyl peptidase-4 inhibitor, linagliptin, ameliorates endothelial dysfunction and atherogenesis in normoglycemic apolipoprotein-E deficient mice. (2016)
  • Author(s): Salim HM, Fukuda D, Higashikuni Y, Kimie Tanaka K, Yoichiro Hirata Y, Yagi S, Soeki T, Shimabukuro M Sata M.
  • Journal Title: Vascular Pharmacology Volume: 79 Pages: 16-23
  • DOI: doi: 10.1016/j.vph.2015.08.011.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance. (2016)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Murata C, Kim-Kaneyama JR, Sato F, Bando M, Yagi S, Soeki T, Hayashi T, Imoto I, Sakaue H, Shimabukuro M, Sata M.
  • Journal Title: Science Advances Volume: 2 Pages: e1501332
  • DOI: doi: 10.1126/sciadv.1501332.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Combination of n-3 polyunsaturated fatty acids reduces atherogenesis in apolipoprotein E-deficient mice by inhibiting macrophage activation. (2016)
  • Author(s): Takashima A, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Nishimoto S, Yagi S, Yamada H, Soeki T, Wakatsuki T, Taketani Y, Shimabukuro M, Sata M.
  • Journal Title: Atherosclerosis Volume: 254 Pages: 142-150
  • DOI: doi: 10.1016/j.atherosclerosis.2016.10.002.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Glycemic Control with Ipragliflozin, a Novel Selective SGLT2 Inhibitor, Ameliorated Endothelial Dysfunction in Streptozotocin-Induced Diabetic Mouse. (2016)
  • Author(s): Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M Sata M.
  • Journal Title: Frontiers in Cardiovascular Medicine Volume: 3 Pages: 43
  • DOI: doi: 10.3389/fcvm.2016.00043.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. (2016)
  • Author(s): Iwata H, Goettsch C, Sharma A, Ricchiuto P, Goh WW, Halu A, Yamada I, Yoshida H, Hara T, Wei M, Inoue N, Fukuda D, Mojcher A, Mattson PC, Barabasi AL, Boothby M, Aikawa E, Singh SA, Aikawa M.
  • Journal Title: Nature Communications Volume: 7 Pages: 12849
  • DOI: doi: 10.1038/ncomms12849.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Delta-Like Ligand 4-Notch Signaling in Macrophage Activation. (2016)
  • Author(s): Nakano T, Fukuda D, Koga JI, Aikawa M.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 36 Pages: 2038-2047
  • DOI: doi.org/10.1161/ATVBAHA.116.306926.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The pathophysiological role of oxidized cholesterols in epicardial fat accumulation and cardiac dysfunction: a study in swine fed a high caloric diet with an inhibitor of intestinal cholesterol absorption, ezetimibe. (2016)
  • Author(s): Shimabukuro M, Okawa C, Yamada H, Yanagi S, Uematsu E, Sugasawa N, Kurobe H, Hirata Y, Kim-Kaneyama JR, Lei XF, Takao S, Tanaka Y, Fukuda D, Yagi S, Soeki T, Kitagawa T, Masuzaki H, Sato M, Sata M.
  • Journal Title: The Journal of Nutritional Biochemistry Volume: 35 Pages: 66-73
  • DOI: doi: 10.1016/j.jnutbio.2016.05.010.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-chain monounsaturated fatty acid-rich fish oil attenuates the development of atherosclerosis in mouse models. (2016)
  • Author(s): Yang ZH, Bando M, Sakurai T, Chen Y, Emma-Okon B, Wilhite B, Fukuda D, Pryor BV, Wakabayashi Y, Sampson M, Yu ZX, Sakurai A, Zarzour A, Miyahara H, Takeo J, Sakaue H, Sata M, Remaley AT.
  • Journal Title: Molecular Nutrition & Food Research Volume: 60 Pages: 2208-2218
  • DOI: doi: 10.1002/mnfr.201600142.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Depot- and gender-specific expression of NLRP3 inflammasome and toll-like receptors in adipose tissue of cancer patients. (2016)
  • Author(s): Shimabukuro M, Sato H, Izaki H, Fukuda D, Uematsu E, Hirata Y, Yagi S, Soeki T, Sakaue H, Kanayama HO, Masuzaki H, Sata M.
  • Journal Title: Biofactors Volume: 42 Pages: 397-406
  • DOI: doi: 10.1002/biof.1287.
  • Peer Reviewed
• [Journal Article] Noninvasive quantitative tissue characterization of carotid plaque using color-coded mapping based on ultrasound integrated backscatter. (2016)
  • Author(s): Bando M, Yamada H, Kusunose K, Fukuda D, Amano R, Tamai R, Torii Y, Hirata Y, Nishio S, Satomi J, Nagahiro S, Sata M.
  • Journal Title: JACC Cardiovasc Imaging Volume: 9 Pages: 625-627
  • DOI: -
  • Peer Reviewed
• [Presentation] Activated Factor X Signaling Pathway via Protease-Activated Receptor-2 is a Novel Therapeutic Target to Prevent Atrial Fibrillation. (2017)
  • Author(s): 谷口実佑、添木武、松浦朋美、佐藤裕紀、飛梅威、原知也、楠瀬賢也、伊勢孝之、山口浩司、八木秀介、福田大受、山田博胤、若槻哲三、島袋充生、佐田政隆
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] The Tissue Characteristics of Coronary Plaque with Microluminal Structures Identified by OCT Associated with Local Inflammatory Response in Fresh Cadavers. (2017)
  • Author(s): 若槻哲三、山口浩司、伊藤浩敬、福田大受、川端豊、轟貴史、松浦朋美、伊勢孝之、楠瀬賢也、飛梅威、八木秀介、山田博胤、添木武、佐田政隆
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Lipid-rich Coronary Plaque is Associated with Local Inflammation in Adjacent Epicardial Adipose Tissue in Fresh Cadaveric Models. (2017)
  • Author(s): 伊藤浩敬、若槻哲三、山口浩司、福田大受、川端豊、轟貴史、松浦朋美、楠瀬賢也、伊勢孝之、飛梅威、八木秀介、山田博胤、添木武、佐田政隆
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Cell free DNA/Toll-like receptor 9 axis plays a pivotal role in chronic inflammation induced by metabolic disorders, leading to atherogenesis and insulin resistance. (2016)
  • Author(s): Fukuda D, Nishimoto S, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: 19th International Vascular Biology Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-10-30 – 2016-11-03
  • Int'l Joint Research
• [Presentation] Genetic deletion of TLR9 promotes blood flow recovery in hind limb ischemia. (2016)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Sakaue H, Shimabukuro M, Sata M.
  • Organizer: 19th International Vascular Biology Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-10-30 – 2016-11-03
  • Int'l Joint Research
• [Presentation] Glycemic control with canagliflozin, a SGLT2 inhibitor, inhibited inflammation in the vascular and adipose tissue, and ameliorated vascular complication in diabetic mice. (2016)
  • Author(s): Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: 19th International Vascular Biology Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-10-30 – 2016-11-03
  • Int'l Joint Research
• [Presentation] Dabigatran, a direct thrombin inhibitor, prevents the development of endothelial dysfunction in diabetic mice. (2016)
  • Author(s): Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: 19th International Vascular Biology Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-10-30 – 2016-11-03
  • Int'l Joint Research
• [Presentation] 遊離核酸断片による血管の炎症と動脈硬化症発症機序の解明 (2016)
  • Author(s): 福田大受、佐田政隆
  • Organizer: 第39回日本高血圧学会総会
  • Place of Presentation: 仙台国際センター （仙台市、宮城県）
  • Year and Date: 2016-09-30 – 2016-10-02
• [Presentation] 動脈硬化発症におけるFXa-PARsシグナルのマクロファージ活性化調節機構の解明 (2016)
  • Author(s): 福田大受
  • Organizer: 第64回日本心臓病学会学術集会
  • Place of Presentation: 東京国際フォーラム （千代田区、東京都）
  • Year and Date: 2016-09-23 – 2016-09-25
• [Presentation] Glycemic Control with Ipragliflozin, a Novel Selective SGLT2 Inhibitor, Ameliorated Endothelial Dysfunction in Obese and Non-Obese Diabetic Mice. (2016)
  • Author(s): Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M.
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27 – 2016-08-31
  • Int'l Joint Research
• [Presentation] Oral Direct Factor Xa Inhibitor Prevents Atrial Fibrillation by Inhibiting Inflammation in Rapidly Paced Spontaneously Hypertensive Rats. (2016)
  • Author(s): Matsuura T, Soeki T, Uematsu E, Bando S, Tobiume T, Hara T, Kusunose K, Ise T, Yamaguchi K, Yagi S, Fukuda D, Yamada H, Wakatsuki T, Shimabukuro M, Sata M.
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27 – 2016-08-31
  • Int'l Joint Research
• [Presentation] Adipocyte size distribution and depot-specific modulation of pro- and anti-atherosclerotic adipocytokines and innate immune molecules in human adipose tissue. (2016)
  • Author(s): Shimabukuro M, Sato H, Izaki H, Fukuda D, Uematsu E, Hirata Y, Yagi S, Soeki T, Sakaue H, Kanayama H, Masuzaki H, Sata M.
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27 – 2016-08-31
  • Int'l Joint Research
• [Presentation] Increased local production of C-type natriuretic peptide in patients with vasospastic angina. (2016)
  • Author(s): Soeki T, Matsuura T, Uematsu E, Bando S, Tobiume T, Kusunose K, Ise T, Yamaguchi K, Yagi S, Fukuda D, Yamada H, Wakatsuki T, Shimabukuro M, Sata M.
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27 – 2016-08-31
  • Int'l Joint Research
• [Presentation] Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance. (2016)
  • Author(s): 福田大受
  • Organizer: 第21回アディポサイエンス・シンポジウム
  • Place of Presentation: 千里ライフサイエンスセンター （豊中市、大阪府）
  • Year and Date: 2016-08-20 – 2016-08-20
• [Presentation] ～心不全を予防する～ 遊離核酸断片を介した血管の炎症と動脈硬化症発症機序の解明. (2016)
  • Author(s): 福田大受、佐田政隆
  • Organizer: 第２回J-ISCP学術集会
  • Place of Presentation: 阿波観光ホテル （徳島市、徳島県）
  • Year and Date: 2016-06-25 – 2016-06-26
• [Presentation] Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in ApoE-Deficient Mice. (2016)
  • Author(s): 福田大受
  • Organizer: 第38回血栓止血学会学術集会
  • Place of Presentation: 奈良春日野国際フォーラム 甍～I・RA・KA～ (奈良市、奈良県)
  • Year and Date: 2016-06-16 – 2016-06-18