Angiopoietin-1-mediated vascular development and maturation in the developing heart

• Project/Area Number: 25293183
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute (2015); Osaka University
• 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): YAMASHITA JUN 京都大学, 再生医科学研究所/iPS細胞研究所, 教授 (50335288) ; KOMURO ISSEI 東京大学医学系研究科, 循環器内科学, 教授 (30260483)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2013: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: angiopoietin-1 / 冠静脈 / 静脈洞 / 内皮細胞 / 血管形成 / 静脈分化 / アンジオポイエチン１ / 冠動脈 / 血管新生 / 心筋梗塞 / COUP-TFII / APJ / 静脈 / 冠血管 / 動脈 / 血管成熟化

Outline of Final Research Achievements

The origin and developmental mechanisms underlying coronary vessels are not fully elucidated. Here we examined the role of myocardium-derived angiopoietin-1 (Ang1) for coronary vessel formation in the developing heart. Cardiomyocyte-specific Ang1 deletion results in defective formation of the subepicardial coronary veins, but had no significant effect on the formation of intramyocardial coronary arteries. The endothelial cells (ECs) of the sinus venosus (SV) are heterogeneous population, composed of APJ-positive and APJ-negative ECs. Among these, the APJ-negative ECs migrate from the SV into the atrial and ventricular myocardium in Ang1-dependent manner. In addition, Ang1 may positively regulate venous differentiation of the subepicardial APJ-negative ECs in the heart. Consistently, in vitro experiments show that Ang1 indeed promotes venous differentiation of the immature ECs. Taken together, these data indicate that myocardial Ang1 is essential for coronary vein formation.

Research Products

• [Int'l Joint Research] KAIST(韓国)
• [Int'l Joint Research] King's College London(英国)
• [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． (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: Am J Physiol Gastrointest Liver Physiol Volume: 308 Issue: 7 Pages: 613-624
  • DOI: 10.1152/ajpgi.00289.2014
  • 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
• [Journal Article] Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart (2014)
  • Author(s): Arita Y, Nakaoka Y, Matsunaga T, Kidoya H, Yamamizu K, Arima Y, Kataoka-Hashimoto T, Ikeoka K, Yasui T, Masaki T, Yamamoto K, Higuchi K, Park JS, Shirai M, Nishiyama K, Yamagishi H, Otsu K, Kurihara H, Minami T, Yamauchi-Takihara K, Koh GY, Mochizuki N, Takakura N, Sakata Y, Yamashita JK, Komuro I
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 4452-4452
  • DOI: 10.1038/ncomms5552
  • Peer Reviewed / Open Access
• [Journal Article] Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity. (2014)
  • Author(s): Park DY, Lee J, Park I, Choi D, Lee S, Song S, Hwang Y, Hong KY, Nakaoka Y, Makinen T, Kim P, Alitalo K, Hong YK, Koh GY.
  • Journal Title: Journal of Clinical Investigation Volume: 24 Issue: 9 Pages: 3960-74
  • DOI: 10.1172/jci75392
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neureguiln-1/ErbBシグナルの心血管系における生理機能 (2014)
  • Author(s): 中岡良和
  • Journal Title: 医学のあゆみ Volume: 250 Pages: 200-206
• [Journal Article] 大型血管炎の標準治療 (2014)
  • Author(s): 中岡良和
  • Journal Title: Modern Physician～臨床医のための血管炎の知識up-to-date Volume: 34 Pages: 1034-1039
• [Journal Article] 野本論文に対するEditorial Comment-難治性高安動脈炎に対する抗IL-6レセプター抗体Tocilizumabの有効性について (2014)
  • Author(s): 中岡良和
  • Journal Title: 心臓 Volume: 46 Pages: 1592-1593
  • NAID: 130005113470
• [Journal Article] Tocilizumab for the treatment of patients with refractory takayasu arteritis. (2013)
  • Author(s): Nakaoka Y, Higuchi K, Arita Y, Otsuki M, Yamamoto K, Hashimoto-Kataoka T, Yasui T, Ikeoka K, Ohtani T, Sakata Y, Shima Y, Kumanogoh A, Yamauchi-Takihara K, Tanaka T, Kishimoto T, Komuro I.
  • Journal Title: International Heart Journal Volume: 54 Pages: 405-411
  • NAID: 130003383361
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 guides directional angiogenesis through integrin αvβ5 signaling for recovery of ischemic retinopathy. (2013)
  • Author(s): Lee J, Kim KE, Choi DK, Jang JY, Jung JJ, Kiyonari H, Shioi G, Chang W, Suda T, Mochizuki N, Nakaoka Y, Komuro I, Yoo OJ, Koh GY.
  • Journal Title: Sci Transl Med. Volume: 5 Issue: 203
  • DOI: 10.1126/scitranslmed.3006666
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 Suppresses Choroidal Neovascularization and Vascular Leakage. (2013)
  • Author(s): Lee J, Park DY, Park DY, Park I, Chang W, Nakaoka Y, Komuro I, Yoo OJ, Koh GY.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: in press Issue: 4 Pages: 2191-2199
  • DOI: 10.1167/iovs.14-13897
  • Peer Reviewed
• [Journal Article] 高安動脈炎の診断と治療 -生物学的製剤による治療の現状に焦点を当てて (2013)
  • Author(s): 中岡良和
  • Journal Title: 医学のあゆみ Volume: 246 Pages: 5-11
• [Journal Article] Interleukin-6 シグナル制御による肺動脈性肺高血圧症の治療の可能性 (2013)
  • Author(s): 中岡良和
  • Journal Title: 日本循環器学会専門医誌 循環器専門医 Volume: 21 Pages: 271-276
• [Journal Article] 影山論文に対するEditorial Comment - 冠動脈・大動脈疾患を合併する巨細胞性動脈炎では厳密な慢性炎症のコントロールに留意する必要がある (2013)
  • Author(s): 中岡良和
  • Journal Title: 心臓 Volume: 45 Pages: 1293-1294
  • NAID: 130004716912
• [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: 第一回J-JSCP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
• [Presentation] IL-6はTh17反応とM2極性化を介して (2014)
  • Author(s): 片岡崇弘
  • Organizer: 第2回肺高血圧学会、第3回肺循環学会
  • Place of Presentation: 大手町サンケイプラザ
  • Year and Date: 2014-10-04
• [Presentation] 難治性高安動脈炎に対するトシリズマブによるinterleukin-6阻害療法による治療の試み (2014)
  • Author(s): 中岡良和
  • Organizer: 日本心臓病学会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2014-09-26
• [Presentation] Angiopoietin-1 derived from myocardium has a critical role for coronary vein formation in the developing heart (2014)
  • Author(s): Yoh Arita
  • Organizer: 8th International Kloster Seeon Meeting
  • Place of Presentation: Kloster Seeon(ドイツ・バイエルン州）
  • Year and Date: 2014-09-20 – 2014-09-23
• [Presentation] Interleukin-6 promotes hypoxia-induced pulmonary arterial hypertension through Th17 response and alternative activation of macrophages (2014)
  • Author(s): Yoshikazu Nakaoka
  • Organizer: 8th International Kloster Seeon Meeting
  • Place of Presentation: Kloster Seeon(ドイツ・バイエルン州）
  • Year and Date: 2014-09-20 – 2014-09-23
• [Presentation] The role of angiopoietin-1 in coronary vessel formation in the developing heart (2014)
  • Author(s): Yoshikazu Nakaoka
  • Organizer: 第18回国際血管生物学会（IVBM2014)
  • Place of Presentation: 京都みやこめっせ
  • Year and Date: 2014-04-14
  • Invited
• [Presentation] 難治性高安動脈炎に対するトシリズマブの安全性と有効性の検討 (2014)
  • Author(s): 中岡良和
  • Organizer: 第111回 日本内科学会総会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2014-04-09
• [Presentation] Tocilizumab Ameliorates Vascular Inflammation and Clinical Symptoms in the Patients with Takayasu Arteritis Refractory to Glucocorticoids
  • Author(s): Yoshikazu Nakaoka, Yoh Arita, Kaori Higuchi, Takahiro Hashimoto-Kataoka, Taku Yasui, Yasushi Sakata, Keiko Yamauchi-Takihara, Tadamitsu Kishimoto, Issei Komuro
  • Organizer: 第30回国際心臓研究学会（ISHR）日本部会総会
  • Place of Presentation: La Valencia Hotel, San Diego, USA
• [Presentation] 抗Interleukin-6(IL-6)受容体抗体によるIL-6阻害療法は低酸素誘発性肺高血圧の病態形成を抑制する
  • Author(s): 中岡良和、橋本崇弘、曽野部崇、瀧原圭子、白井幹康、小室一成
  • Organizer: 第2回日本肺循環学会学術集会
  • Place of Presentation: 東京ステーションコンファレンス(東京都千代田区)
  • Invited
• [Presentation] Angiopoietin-1 is essential for coronary venogenesis in the developing heart
  • Author(s): 中岡 良和
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Invited
• [Presentation] 血管形成研究の最前線「冠静脈形成の分子機構
  • Author(s): 中岡良和、有田陽、松永太一、山下潤、小室一成
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 千里阪急ホテル(大阪府豊中市)
• [Presentation] 心筋由来のAngiopoietin-1は静脈洞内皮細胞の遊走と静脈分化の促進を通して冠静脈
  • Author(s): 中岡良和、有田陽、小室一成
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Invited
• [Presentation] Tocilizumab Ameliorates Vascular Inflammation and Clinical Symptoms in the Patients with Takayasu Arteritis Refractory to Glucocorticoids
  • Author(s): Yoshikazu Nakaoka, Kaori Higuchi, Yoh Arita, Taku Yasui, Kuniyasu Ikeoka, Takeshi Masaki,Tomohito Ohtani, Keiko Yamauchi-Takihara, Yasushi Sakata, Issei Komuro
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
• [Presentation] 心臓における冠血管発生
  • Author(s): 中岡 良和
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 国立京都国際会館(京都府京都市)
  • Invited
• [Presentation] Angiopoietin-1 secreted from myocardium is essential for the formation of coronary veins in the developing heart
  • Author(s): Yoh Arita, Yoshikazu Nakaoka, Taichi Matsunaga, Hiroyasu Kidoya, Kohei Yamamizu, Yuichiro Arima, Kaori Higuchi, Takahiro Hashimoto, Kuniyasu Ikeoka, Taku Yasui, Koichi Nishiyama, Hiroki Kurihara, Keiko Yamauchi-Takihara, Hiroyuki Yamagishi, Nobuyuki Takakura, Naoki Mochizuki, Gou Young
  • Organizer: 第30回国際心臓研究学会(ISHR)日本部会総会
  • Place of Presentation: La Valencia Hotel, San Diego, USA
• [Presentation] 血管平滑筋細胞由来のアンジオポエチン１は下肢虚血血管新生時の動脈化に重要である
  • Author(s): 池岡邦泰、中岡良和、曽野部崇、白井幹康、樋口香織、有田陽、片岡崇弘、安居琢、正木豪、瀧原圭子、小室一成
  • Organizer: 第4回Molecular Cardiovascular ConferenceII
  • Place of Presentation: キロロリゾートホテルピアノ(北海道余市郡赤井川村)
• [Presentation] アンギオポイエチン1は静脈洞の未分化血管内皮細胞を遊走・分化させ冠静脈形成に必須の因子である
  • Author(s): 有田陽、中岡良和、松永太一、木戸屋浩康、橋本崇弘、池岡邦泰、高倉伸幸、望月直樹、山下潤、小室一成
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 千里阪急ホテル(大阪府豊中市)
• [Presentation] 血管平滑筋細胞由来のアンジオポエチン１は下肢虚血血管新生時の動脈化に重要である
  • Author(s): 池岡邦泰、中岡良和、曽野部崇、白井幹康、樋口香織、有田陽、片岡崇弘、安居琢、正木豪、瀧原圭子、小室一成
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 千里阪急ホテル(大阪府豊中市)
• [Presentation] Angiopoietin-1 Derived from Vascular Smooth Muscle Cells is Essential for Arteriogenesis after Hindlimb Ischemia
  • Author(s): Kuniyasu Ikeoka, Yoshikazu Nakaoka, Takashi Sonobe, Kaori Higuchi, Yoh Arita, Takahiro Hashimoto-Kataoka, Taku Yasui, Takeshi Masaki, Stephan Offermans, Keiko Yamauchi-Takihara, Mikiyasu Shirai, Issei Komuro
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
• [Book] Annual Review 2016循環器 (2016)
  • Author(s): 中岡良和
  • Total Pages: 8
  • Publisher: 中外医学社
• [Remarks] 心臓の血管新生の新メカニズムを解明
  • URL: http://resou.osaka-u.ac.jp/ja/research/2014/20140722_1
• [Remarks] 大阪大学医学系研究科循環器内科学心血管サイトカイングループHP
  • URL: http://www.cardiology.med.osaka-u.ac.jp/?page_id=66
• [Remarks] 大阪大学大学院医学系研究科循環器内科学心血管サイトカイン研究グループ
  • URL: http://www.med.osaka-u.ac.jp/pub/cardiology/27research/2751res.html
• [Patent(Industrial Property Rights)] 肺高血圧症治療薬およびそのスクリーニング法 (2014)
  • Inventor(s): 中岡良和、片岡崇弘
  • Industrial Property Rights Holder: 中岡良和、片岡崇弘
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-09-08