Molecular mechanism of Vasculitis and Pulmonary arterial hypertension via inflammatory cytokines

• Project/Area Number: 15K15309
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Nakaoka Yoshikazu 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (90393214)
• Co-Investigator(Renkei-kenkyūsha): SHIRAI MIKIYASU 国立循環器病研究センター, 研究所, 特任研究員 (70162758) ; HOSEN NAOKI 大阪大学, 大学院医学系研究科, 准教授 (10456923)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 炎症 / サイトカイン / 肺動脈性肺高血圧症 / 高安動脈炎 / interleukin-6 / interleukin-21 / IL-6 / IL-21 / 肺高血圧症 / トランスジェニックマウス

Outline of Final Research Achievements

We aimed to elucidate the molecular mechanisms of intractable　vascular　diseases　such　as　Takayasu　arteritis　(TAK) or　pulmonary　arterial　hypertension　(PAH) in this study.　We tried to create the animal models of these diseases which mimic the pathologies of these diseases through overexpression of the key inflammatory cytokines in the aortic endothelium or lung epithelium. We hypothesized that inflammatory cytokines including interleukin-6 (IL-6) or IL-21 are important for development of TAK of PAH, and created the mice which harbor the TetO-mIL-6 or TetO-mIL-21 genes in C57BL6 mice for creation of PAH model mice. And, we also created transgenic mice which harbor either BMX-mIL-6 or BMX-mIL-21. Until now, we could not succeed in creating the above transgenic mice which overexpress mIL-6 or mIL-21 either in aortic endothelium or in lung epithelium. We are now adjusting the overexpression condition in the above TG mice.

Research Products

• [Journal Article] Fibrosis Through Activation of PKA Signaling in Hypertrophired Heart. (2017)
  • Author(s): Wang Q,Oka T,Yamagami K,Lee JK,Akazawa H,Naito AT,Yasui T,Ishizu T,Nakaoka Y,Sakata Y,Komuro I.
  • Journal Title: International Heart Journal Volume: 58 Pages: 107-114
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular Characterization of Striated Muscle-specific Gab1Isoform as aCritical Signal Transducer for Neuregulin-1/ErbB Signaling in Cardiomyocytes. (2016)
  • Author(s): Yasui T,Masaki T,Arita Y,Ishibashi T,Inagaki T,Okazawa M,Oka T,Shioyama W,Yamauchi-Takihara K,Komuro I,Sakata Y,Nakaoka Y.
  • Journal Title: PlosOne Volume: 11 Issue: 11 Pages: e0166710-e0166710
  • DOI: 10.1371/journal.pone.0166710
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Amelioration of sepsis by TIE2 activation-induced vascular protection. (2016)
  • Author(s): Han S,Lee SJ,Kim KE,Lee HS,Oh N,Park I,Ko E,Oh SJ,Kim HC,Kim SKim SH,Kim C,Nakaoka Y,He Y,Augustin HG,Hu J,Song PH,Kim YI,Kim P,Kim I,Koh GY.
  • Journal Title: Science Translation Medicine Volume: 8 Issue: 335 Pages: 335-355
  • DOI: 10.1126/scitranslmed.aad9260
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice. (2016)
  • Author(s): Furuta K, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Maeda S, Egawa M, Chatani N, Nishida K, Nakaoka Y, Kiso S, Kamada Y, Takehara T.
  • Journal Title: Hepatology Volume: 63 Issue: 4 Pages: 1340-1355
  • DOI: 10.1002/hep.28410
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 肺高血圧症におけるサイトカインネットワーク．分子呼吸器病 (2016)
  • Author(s): 中岡良和
  • Journal Title: 分子呼吸器病 Volume: 20 Pages: 73-76
• [Journal Article] Cytokine storm after cessation of tocilizumab in a patient with refractory Takayasu arteritis. (2015)
  • Author(s): Arita Y, Nakaoka Y, Otsuki M, Higuchi K, Hashimoto-Kataoka T, Yasui T, Masaki T, Ohtani T, Kishimoto T, Yamauchi-Takihara K, Komuro I, Sakata Y.
  • Journal Title: International Journal of Cardiology Volume: 187 Pages: 319-321
  • DOI: 10.1016/j.ijcard.2015.03.399
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gab1 Is Modulated by Chronic Hypoxia in Children with Cyanotic Congenital Heart Defect and Its Overexpression Reduces Apoptosis in Rat Neonatal Cardiomyocytes. (2015)
  • Author(s): Cherif M., Caputo M, Nakaoka Y, Angelini G, Ghorbel M.
  • Journal Title: BioMed Research International. Volume: 101155 Pages: 718492-718492
  • DOI: 10.1155/2015/718492
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension (2015)
  • Author(s): Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masaki T, Minami M, Inagaki T, Miyagawa S, Sawa Y, Murakami M, Kumanogoh A, Yamauchi-Takihara K, Okumura M, Kishimoto T, Komuro I, Shirai M, Sakata Y, and Nakaoka Y
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: Early Edition Issue: 20 Pages: 1-10
  • DOI: 10.1073/pnas.1424774112
  • Peer Reviewed / Open Access
• [Journal Article] Takayasu arteritis and ulcerative colitis -high concurrence ratio and genetic overlap. (2015)
  • Author(s): Terao C, Matsumura T, Yoshifuji H, Kirino Y, Maejima Y, Kochi Y, Ogimoto A, Yamamoto M, Takahashi H, Nakayamada S, Saito K, Wada Y, Narita I, Kawaguchi Y, Yamanaka H, Ohmura K, Atsumi T, Tanemoto K, Miyata T, Kuwana M, Komuro I, Tabara Y, Ueda A, Isobe M, Mimori T, Matsuda F.
  • Journal Title: Arthritis Rheumatol. Volume: - Issue: 8 Pages: 2226-2232
  • DOI: 10.1002/art.39157
  • Peer Reviewed
• [Journal Article] Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice. (2015)
  • Author(s): Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Takemura T, Ezaki H, Kamada Y, Nishida K, Nakaoka Y, Kiso S, Takehara T.
  • Journal Title: American journal of physiology.Gastrointestinal and liver physiology. Volume: 308
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 高安動脈炎 (2015)
  • Author(s): 中岡良和
  • Journal Title: 循環器内科 Volume: 78 Pages: 366-373
• [Journal Article] 高安動脈炎と抗IL-6受容体療法 (2015)
  • Author(s): 中岡良和
  • Journal Title: 感染 炎症 免疫 Volume: 45 Pages: 262-265
• [Journal Article] IL-6による肺高血圧症の病態形成の分子機構 (2015)
  • Author(s): 中岡良和
  • Journal Title: Pulmonary Hypertension Update Volume: 1 Pages: 62-67
• [Presentation] Ｉｎｔｅｒｌｅｕｋｉｎ－６／ｉｎｔｅｒｌｅｕｋｉｎ－２１－ｓｉｇｎａｌｉｎｇａｘｉｓ ｐｌａｙｓ ａ ｃｒｉｔｉｃａｌ ｒｏｌｅ ｉｎ ｔｈｅ pathogenesis of pulmonary arterial hypertension. (2016)
  • Author(s): 中岡良和
  • Organizer: 第24回日本血管生物医学会総会シンポジウム
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2016-12-10
• [Presentation] Ｃｒｉｔｉｃａｌ ｒｏｌｅｓ ｏｆ ｉｎｔｅｒｌｅｕｋｉｎ－６／ｉｎｔｅｒｌｅｕｋｉｎ－２１－ｓｉｇｎａｌｉｎｇ ａｘｉｓ ｉｎ ｔｈｅ ｐａｔｈｏｇｅｎｅｓｉｓ ｏｆ ｐｕｌｍｏｎａｒｙ ａｒｔｅｒｉａｌ ｈｙｐｅｒｔｅｎｓｉｏｎ． (2016)
  • Author(s): 中岡 良和
  • Organizer: 第39回日本分子生物学会年会シンポジウム
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] 2016 Oral presentation;Efficacy and Safety of Tocilizumab in patients with refractory Takayasu Arteritis:Results from randomized double-blind placebo-controlled trial in Japan. (2016)
  • Author(s): Nakaoka Y
  • Organizer: American College of Rheumatology (ACR)
  • Place of Presentation: ワシントンＤＣ
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] 炎症性シグナルに焦点を当てた肺高血圧の病態形成機構. (2016)
  • Author(s): 中岡良和
  • Organizer: 第1回日本肺高血圧・肺循環器学会総会・学術集会シンポジウム
  • Place of Presentation: 京王プラザホテル
  • Year and Date: 2016-10-02
• [Presentation] 炎症性サイトカインによる肺高血圧症の病態形成機構 (2016)
  • Author(s): 中岡良和
  • Organizer: 第2回Ｊ－ＩＳＣＰ(日本薬物療法学会）学術集会.
  • Place of Presentation: 阿波観光ホテル
  • Year and Date: 2016-06-26
• [Presentation] 大型血管炎の診療ガイドライン (2016)
  • Author(s): 中岡良和
  • Organizer: 第60回日本リウマチ学会総会・学術集会シンポジウム
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-04-21
  • Invited
• [Presentation] A novel cardiomyocyte-specific isoform of docking protein Gab1 plays a critical role in neuregulin-1/ErbB signaling (2016)
  • Author(s): 安居琢,,山本かおり,有田陽,片岡崇弘,正木豪,小室一成,坂田泰史,中岡良和
  • Organizer: 日本循環器学会
  • Place of Presentation: "せんだい青葉山交流広場 特設会場
  • Year and Date: 2016-03-19
• [Presentation] A novel cardiomyocyte-specific isoform of docking protein Gab1 plays a critical role in neuregulin-1/ErbB signaling (2015)
  • Author(s): 安居琢,有田陽,瀧原圭子,小室一成,坂田泰史,中岡良和
  • Organizer: ISHR日本部会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-11
• [Presentation] A novel cardiomyocyte-specific isoform of docking protein Gab1 plays a critical role in neuregulin-1/ErbB signaling (2015)
  • Author(s): 安居琢,山本かおり,有田陽,片岡崇弘,正木豪,小室一成,坂田泰史,中岡良和
  • Organizer: MCCⅡ
  • Place of Presentation: ヒルトン福岡シーホーク
  • Year and Date: 2015-09-04
• [Presentation] Interleukin-6/interleukin-21 signaling axis in the pathogenesis of pulmonary arterial hypertension (2015)
  • Author(s): 中岡良和
  • Organizer: 第21回日本遺伝子治療学会学術集会（血管生物医学会合同シンポジウム・血管生物学のフロンティア）
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2015-07-25
• [Presentation] 炎症制御で血管病を治療する (2015)
  • Author(s): 中岡良和
  • Organizer: 日本NO学会アフタヌーンセミナー
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 2015-06-27
  • Invited
• [Presentation] 難治性高安動脈炎に対する抗interleukin-6受容体抗体トシリズマブによる治療の試み (2015)
  • Author(s): 正木豪,中岡良和,有田陽,片岡崇弘,安居琢,大谷朋仁,瀧原圭子,坂田泰史
  • Organizer: 第１回Ｊ－ＩＳＣＰ学術集会 国際心血管薬物療法学会日本部会
  • Place of Presentation: ハイアットリージェンシー京都
  • Year and Date: 2015-06-20
• [Presentation] Angiopoietin-1 derived from myocardium is essential for coronary vein formation in the developing heart (2015)
  • Author(s): 中岡良和
  • Organizer: 日本血管生物医学会春季特別シンポジウム
  • Place of Presentation: 大阪大学微生物病研究所谷口記念講堂
  • Year and Date: 2015-05-13
  • Invited
• [Presentation] The Role of Angiopoietin-1 in Coronary Venogenesis in the Developing Heart (2015)
  • Author(s): 中岡良和
  • Organizer: 日本循環器学会 会長特別企画シンポ・心臓の発生と再生
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2015-04-25
• [Book] Annual Review ２０１６循環器 (2016)
  • Author(s): 中岡良和
  • Total Pages: 8
  • Publisher: 中外医学社
• [Book] 循環器病研究の進歩 (2016)
  • Author(s): 中岡良和
  • Total Pages: 7
  • Publisher: 協和企画
• [Book] Annual Review 2016循環器 (2016)
  • Author(s): 中岡良和
  • Total Pages: 8
  • Publisher: 中外医学社
• [Remarks] 国立循環器病研究センター研究所血管生理学部
  • URL: http://www.ncvc.go.jp/res/divisions/vascular_physiology/
• [Remarks] 心不全につながる難病 肺高血圧症の発症メカニズムを解明
  • URL: http://www.jst.go.jp/pr/announce/20150505/