A study to elucidate the mechanism by which sterile chronic inflammation occurs in arterial wall and perivascular adipose tissue

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16H05299
• Research Institution: The University of Tokushima
• Principal Investigator: 佐田 政隆 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (80345214)
• Co-Investigator(Kenkyū-buntansha): 平田 陽一郎 東京大学, 医学部附属病院, 助教 (40447397) ; 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) ; 添木 武 徳島大学, 大学院医歯薬学研究部(医学系), 准教授 (60393211)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 動脈硬化 / 自然免疫 / インスリン抵抗性 / 生活習慣病

Outline of Annual Research Achievements

生活習慣病によって生じる動脈硬化やメタボリックシンドロームが、慢性炎症を基盤にがしていることが解明されているが、無菌的な慢性炎症が生じる機序については不明な点が多く、その分子機序について検討を行った。
１．肥満に伴って脂肪組織から、cfDNAが放出された。そして、TLR9がcfDNAによって活性化され、脂肪組織での慢性炎症ならびにインスリン抵抗性が引き起こした。TLR9欠損マウスでは、脂肪組織での炎症が減弱しており、肥満に伴うインスリン抵抗性が軽減していた。骨髄移植の実験から、骨髄細胞上のTLR9が重要であることが明らかになった。TLR9の阻害オリゴヌクレオチドは、肥満による脂肪組織の炎症とインスリン抵抗性を改善した。
２．動脈硬化発症するApoE欠損マウスでは動脈壁におけるTLR9の発現量が増加しており、主にマクロファージが発現していた。ApoE KOマウスにAng Ⅱを投与したことで、血漿中の1本鎖DNAなどのcfDNAが増加した。ApoE KOとTLR9/ApoE dKO間で体重、血圧、血漿脂質値に差を認めなかったが、TLR9/ApoE dKOマウスの動脈硬化病変およびプラーク内脂質量は、ApoE KOマウスに比べて有意に少なかった。さらに、骨髄移植実験により、血管壁より骨髄のTLR9が重要であることが明らかとなった。LR9の阻害オリゴヌクレオチドは、血管での慢性炎症と動脈硬化を抑制した。
メタボリックシンドロームや動脈硬化における慢性炎症において、cfDNA-TLR9経路は重要な役割を担っており、新たな生活習慣病治療の標的になると考えられた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

肥満、動脈硬化モデルにおいて、自然免疫の果たす役割が順調に解明できている。骨髄移植や臓器特異的な遺伝子改変マウスの作製も順調に進んでいる。

Strategy for Future Research Activity

臓器特異的な遺伝子欠損マウスを用いて、生活習慣病によって、自己DNAをはじめとする内在性リガンドが自然免疫を活性化するメカニズムを明らかにして、治療法の開発へつなげていく。

Research Products

• [Journal Article] Development and validation of optimal cut-off value in inter-arm systolic blood pressure difference for prediction of cardiovascular events (2018)
  • Author(s): Hirono Akira、Kusunose Kenya、Kageyama Norihito、Sumitomo Masayuki、Abe Masahiro、Fujinaga Hiroyuki、Sata Masataka
  • Journal Title: J Cardiol Volume: 71 Pages: 24～30
  • DOI: 10.1016/j.jjcc.2017.06.010
  • Peer Reviewed
• [Journal Article] Edoxaban improves acute venous thromboembolism while preserving protein C and protein S levels (2018)
  • Author(s): Yamazaki Hiromu、Yagi Shusuke、Torii Yuta、Amano Rie、Oomichi Yasuyuki、Sangawa Teruaki、Fukuda Daiju、Kadota Muneyuki、Ise Takayuki、Ueno Rie、Hara Tomoya、Kusunose Kenya、Matsuura Tomomi、Tobiume Takeshi、Yamaguchi Koji、Yamada Hirotsugu、Soeki Takeshi、Wakatsuki Tetsuzo、Akaike Masashi、Sata Masataka
  • Journal Title: J Cardiol Volume: 71 Pages: 305～309
  • DOI: 10.1016/j.jjcc.2017.09.009
  • Peer Reviewed
• [Journal Article] Longitudinal association among endothelial function, arterial stiffness and subclinical organ damage in hypertension (2018)
  • Author(s): Tomiyama Hirofumi、Ishizu Tomoko、Matsumoto Chisa、Higashi Yukihito、Takase Bonpei、Ueda Shinichiro、Kario Kazuomi、Inoue Teruo、Koba Shinji、Takemoto Yasuhiko、Hano Takuzo、Sata Masataka、Ishibashi Yutaka、Node Koichi、Maemura Koji、Ohya Yusuke、Furukawa Taiji、Ito Hiroshi、Yamashina Akira
  • Journal Title: Int J Cardiol Volume: 253 Pages: 161～166
  • DOI: 10.1016/j.ijcard.2017.11.022
  • Peer Reviewed
• [Journal Article] Inhibition of activated factor X by rivaroxaban attenuates neointima formation after wire-mediated vascular injury (2018)
  • Author(s): Hara Tomoya、Fukuda Daiju、Tanaka Kimie、Higashikuni Yasutomi、Hirata Yoichiro、Yagi Shusuke、Soeki Takeshi、Shimabukuro Michio、Sata Masataka
  • Journal Title: Euro J Pharmacol Volume: 820 Pages: 222～228
  • DOI: 10.1016/j.ejphar.2017.12.037
  • Peer Reviewed
• [Journal Article] Provocation of clinically significant left ventricular outflow tract obstruction by postural change in patients with sigmoid septum (2018)
  • Author(s): Hirata Yukina、Yamada Hirotsugu、Kusunose Kenya、Nishio Susumu、Torii Yuta、Horike Yuki、Sata Masataka
  • Journal Title: J Ecocardiogr Volume: - Pages: -
  • DOI: 10.1007/s12574-018-0372-x
  • Peer Reviewed
• [Journal Article] An Occluded Hooklet of an Embedded Inferior Vena Cava Filter (2018)
  • Author(s): Yagi Shusuke、Yamamoto Yousuke、Nishiyama Seiichi、Sata Masataka
  • Journal Title: Intem Med Volume: - Pages: -
  • DOI: 10.2169/internalmedicine.0505-17
  • Peer Reviewed
• [Journal Article] Roles of Perivascular Adipose Tissue in the Pathogenesis of Atherosclerosis (2018)
  • Author(s): Tanaka Kimie、Sata Masataka
  • Journal Title: Frontiers in Physiology Volume: 9 Pages: 3
  • DOI: 10.3389/fphys.2018.00003
  • Peer Reviewed / Open Access
• [Journal Article] α-Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome: a multicenter randomized controlled (MACS) study (2017)
  • Author(s): Shimabukuro Michio、Tanaka Atsushi、Sata Masataka、Dai Kazuoki、Shibata Yoshisato、Inoue Yohei、Ikenaga Hiroki、Kishimoto Shinji、Ogasawara Kozue、Takashima Akira、Niki Toshiyuki、Arasaki Osamu、Oshiro Koichi、Mori Yutaka、Ishihara Masaharu、Node Koichi
  • Journal Title: Cardiovasc Diabetol Volume: 16 Pages: 86
  • DOI: 10.1186/s12933-017-0571-1
  • Peer Reviewed / Open Access
• [Journal Article] RV Myocardial Strain During Pre-Load Augmentation Is Associated With Exercise Capacity in Patients With Chronic HF (2017)
  • Author(s): Kusunose Kenya、Yamada Hirotsugu、Nishio Susumu、Ishii Ayumi、Hirata Yukina、Seno Hiromitsu、Saijo Yoshihito、Ise Takayuki、Yamaguchi Koji、Yagi Shusuke、Soeki Takeshi、Wakatsuki Tetsuzo、Sata Masataka
  • Journal Title: JACC Cardiovasc Imaging Volume: 10 Pages: 1240～1249
  • DOI: 10.1016/j.jcmg.2017.03.022
  • Peer Reviewed
• [Journal Article] Age-related changes in morphology of left atrial appendage in patients with atrial fibrillation (2017)
  • Author(s): Hirata Yukina、Kusunose Kenya、Yamada Hirotsugu、Shimizu Rikuto、Torii Yuta、Nishio Susumu、Saijo Yoshihito、Takao Shoichiro、Soeki Takeshi、Sata Masataka
  • Journal Title: Int J Cardiovasc Imaging Volume: 34 Pages: 321～328
  • DOI: 10.1007/s10554-017-1232-x
  • Peer Reviewed
• [Journal Article] Echocardiographic Epicardial Adipose Tissue Thickness Is Associated with Symptomatic Coronary Vasospasm during Provocative Testing (2017)
  • Author(s): Nishio Susumu、Kusunose Kenya、Yamada Hirotsugu、Hirata Yukina、Ise Takayuki、Yamaguchi Koji、Yagi Shusuke、Soeki Takeshi、Wakatsuki Tetsuzo、Shimabukuro Michio、Sata Masataka
  • Journal Title: J Am Soc Echocardioqr Volume: 30 Pages: 1021～1027
  • DOI: 10.1016/j.echo.2017.06.024
  • Peer Reviewed
• [Journal Article] Low Serum Levels of Eicosapentaenoic Acid and Docosahexaenoic Acid are Risk Factors for Cardiogenic Syncope in Patients with Brugada Syndrome (2017)
  • Author(s): Yagi Shusuke、Soeki Takeshi、Aihara Ken-ichi、Fukuda Daiju、Ise Takayuki、Kadota Muneyuki、Bando Sachiko、Matsuura Tomomi、Tobiume Takeshi、Yamaguchi Koji、Kusunose Kenya、Yamada Hirotsugu、Wakatsuki Tetsuzo、Shimabukuro Michio、Akaike Masashi、Sata Masataka
  • Journal Title: Int Heart J Volume: 58 Pages: 720～723
  • DOI: 10.1536/ihj.16-278
  • Peer Reviewed / Open Access
• [Journal Article] Improved Exercise Capacity After Cardiac Rehabilitation Is Associated with Reduced Visceral Fat in Patients with Chronic Heart Failure (2017)
  • Author(s): Takagawa Yuriko、Yagi Shusuke、Ise Takayuki、Ishii Ayumi、Nishikawa Koji、Fukuda Daiju、Kusunose Kenya、Matsuura Tomomi、Tobiume Takeshi、Yamaguchi Koji、Yamada Hirotsugu、Soeki Takeshi、Wakatsuki Tetsuzo、Shimabukuro Michio、Katoh Shinsuke、Aihara Ken-ichi、Akaike Masashi、Sata Masataka
  • Journal Title: Int Heart J Volume: 58 Pages: 746～751
  • DOI: 10.1536/ihj.16-454
  • Peer Reviewed / Open Access
• [Journal Article] Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus (2017)
  • Author(s): Yagi Shusuke、Hirata Yukina、Ise Takayuki、Kusunose Kenya、Yamada Hirotsugu、Fukuda Daiju、Salim Hotimah Masdan、Maimaituxun Gulinu、Nishio Susumu、Takagawa Yuriko、Hama Saori、Matsuura Tomomi、Yamaguchi Koji、Tobiume Takeshi、Soeki Takeshi、Wakatsuki Tetsuzo、Akaike Masashi、Shimabukuro Michio、Sata Masataka
  • Journal Title: Diabetol Metab Syndr Volume: 9 Pages: 78
  • DOI: 10.1186/s13098-017-0275-4
  • Peer Reviewed
• [Journal Article] Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats (2017)
  • Author(s): Kinouchi Tomoya、Kitazato Keiko T、Shimada Kenji、Yagi Kenji、Tada Yoshiteru、Matsushita Nobuhisa、Kurashiki Yoshitaka、Satomi Junichiro、Sata Masataka、Nagahiro Shinji
  • Journal Title: Transl Stroke Re Volume: - Pages: -
  • DOI: 10.1007/s12975-017-0577-8
  • Peer Reviewed
• [Presentation] Direct Slow Pathway Capture: A New Electrophysiological Method of Catheter Ablation for Atrioventricular Nodal Reentrant Tachycardia (2017)
  • Author(s): Matsuura T, Tobiume T, Soeki T, Kato R, Hara M, Takayuki Ise, Kenya Kusunose, Yamaguchi K, Yagi S, Yamada H, Wakatsuki Tetsuzo , Sata M
  • Organizer: AHA Scientific Sessions2017
  • Int'l Joint Research
• [Presentation] Pre-Discharge LV Filling Pressure and Pulmonary Artery Pressure Were Associated With Hospital Readmission in Heart Failure With Reduced and Preserved Ejection Fraction (2017)
  • Author(s): Torii Y, Kusunose K, Yamada H, Saijo Y, Seno H, Nishio S, Hirata Y, Sata M
  • Organizer: Pre-Discharge LV Filling Pressure and Pulmonary Artery Pressure Were Associated With Hospital Readmission in Heart Failure With Reduced and Preserved Ejection Fraction
  • Int'l Joint Research
• [Presentation] Preserved Endothelial Function and Suppressed Local Coagulative and Inflammatory Response (2017)
  • Author(s): Yamaguchi K, Wakatsuki T, Kawabata Y, Ito H, Matsuura T, Ise T, Kusunose K, Tobiume T, Yagi S, Yamada H, Soeki T, Sata M
  • Organizer: AHA Scientific Sessions2017
  • Int'l Joint Research
• [Presentation] Activated Factor X Signaling Pathway via Protease-Activated Receptor-2 is a Novel Therapeutic Target to Prevent Atrial Fibrillation (2017)
  • Author(s): Takeshi Soeki, Tomomi Matsuura, Daiju Fukuda, Etsuko Uematsu, Takeshi Tobiume, Tomoya Hara, Kenya Kusunose, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Tetsuzo Wakatsuki, Masataka Sata
  • Organizer: AHA Scientific Sessions2017
  • Int'l Joint Research
• [Presentation] Echocardiography Predicts Outcomes in Patients With Preserved Ejection Fraction and Low Gradient Aortic Stenosis (2017)
  • Author(s): Kusunose K, Yamada H, Nishio S, Torii Y, Hirata Y, Seno H, Saijo Y, Ise T, Yamaguchi K, Yagi S, Soeki T, Wakatsuki T, Sata M
  • Organizer: AHA Scientific Sessions2017
  • Int'l Joint Research
• [Presentation] Local Epicardial Adipose Tissue Thickness in Left Anterior Descending Artery Provides a New Prediction Model for Coronary Artery Disease (2017)
  • Author(s): Gulinu Maimaituxun, Shimabukuro M, Hirata Y, Iwase T, Takao S, Matsuura T, Ise T, Kusunose K, Tobiume T, Yamaguchi K, Yagi S, Fukuda D, Yamada H, Soeki T, Wakatsuki T, Harada M, Sata M
  • Organizer: AHA Scientific Sessions2017
  • Int'l Joint Research
• [Presentation] Detection of Coronary Artery Stenosis by Epicardial Adipose Tissue Thickness in Type 2 Diabetes (2017)
  • Author(s): Hirata Y, Kusunose K, Yamada H, Kuwahata J, Torii Y, Nishio S, Seno H, Saijo Y, Yamaguchi K, Wakatsuki T, Sara M
  • Organizer: AHA Scientific Sessions2017
  • Int'l Joint Research
• [Presentation] Epicardial Adipose Tissue Produces Proinflammatory Cytokines and Influences the Pathogenesis of Atrial Fibrillation (2017)
  • Author(s): Soeki T, Matsuura T, Uematsu E, Tobiume T, Kusunose K, Ise T, Yamaguchi K, Yagi S, Fukuda D, Yamada H, Wakatsuki T, Sata M
  • Organizer: AHA Scientific Sessions2017
  • Int'l Joint Research