The molecular mechanism of atherosclerosis through endothelial dysfunction

• Project/Area Number: 23591101
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses (2013); Osaka University (2011-2012)
• Principal Investigator: KURODA TADASHI 地方独立行政法人大阪府立病院機構大阪府立成人病センター(研究所), その他部局等, その他(副部長) (60403078)
• Co-Investigator(Kenkyū-buntansha): NAKAOKA Yoshikazu 大阪大学, 医学(系)研究科(研究院), 助教 (90393214)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 動脈硬化 / 血管炎症 / 内皮 / Gab1 / KLF2 / トランスジェニックマウス / KLF4

Research Abstract

We reported that Gab1 is essential for postnatal angiogenesis through the analysis of endothelium-specific Gab1 knockout (Gab1ECKO) mice. However, the role of Gab1 in atherosclerosis remains unknown. We intercrossed Gab1ECKO mice with ApoE knockout (ApoEKO) mice. Six-month-old male ApoEKO/Gab1ECKO and littermate control (ApoEKO) mice were treated with angiotensin II (AngII) via an osmotic infusion minipump. After AngII treatment, ApoEKO/Gab1ECKO mice showed significantly enhanced atherosclerosis and aneurysm formation compared with control mice. The production of proinflammatory cytokines in the aorta was significantly enhanced in ApoEKO/Gab1ECKO mice compared with control. The expression levels of KLF2 and KLF4 were significantly reduced in the aortic endothelium of ApoEKO/Gab1ECKO mice compared with control. Collectively, endothelial Gab1 deletion accelerates AngII-dependent vascular inflammation and atherosclerosis presumably via downregulation of KLF2 and KLF4.

Research Products

• [Journal Article] A novel homemade snare, safe, economical and size adjustable (2014)
  • Author(s): Yokoi K, Sumitsuji S, Kaneda H, Siegrist P, Okayama K, Ide S, Mizote I, Kumada M, Kuroda T, Tachibana K, Sakata Y, Nanto S
  • Journal Title: EuroIntervention Volume: (Epub ahead of print) Pages: 20130208-1
  • 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] Tocilizumab for the Treatment of the 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: Int Heart J Volume: 54 Pages: 405-411
  • NAID: 130003383361
  • Peer Reviewed
• [Journal Article] Gab docking proteins in cardiovascular disease, cancer, and inflammation (2013)
  • Author(s): Nakaoka Y, Komuro I
  • Journal Title: Int J Inflam Volume: 2013 Pages: 141068-141068
  • DOI: 10.1155/2013/141068
  • Peer Reviewed
• [Journal Article] Alpha-synuclein elicits glucose uptake and utilization in adipocytes through the Gab1/PI3K/Akt transduction pathway. (2013)
  • Author(s): Rodriguez-Araujo G, Nakagami H, Hayashi H, Mori M, Shiuchi T, Minokoshi Y, Nakaoka Y, Takami Y, Komuro I, Morishita R, Kaneda Y
  • Journal Title: Cell Mol Life Sci Volume: 70 Issue: 6 Pages: 1123-1133
  • DOI: 10.1007/s00018-012-1198-8
  • Peer Reviewed
• [Journal Article] 血管リモデリング (2013)
  • Author(s): 中岡良和、小室一成
  • Journal Title: 日本医師会雑誌(特別号・高血圧診療のすべて) Volume: 142(Suppl 1)
• [Journal Article] 高安動脈炎の治療 (2013)
  • Author(s): 中岡良和、瀧原圭子、小室一成
  • Journal Title: 日本臨床(増刊号・血管炎) Volume: 71(Suppl 1) Pages: 173-178
• [Journal Article] 高安動脈炎の診断と治療 (2013)
  • Author(s): 中岡良和
  • Journal Title: 医学のあゆみ(血管炎の診断と治療) Volume: 246 (1) Pages: 5-11
• [Journal Article] Tocilizumab for the Treatment of the Patients with Refractory Takayasu Arteritis (2013)
  • Author(s): Nakaoka Yoshikazu, Higuchi Kaori, Arita Yoh, Otsuki Michio, Yamamoto Kaori, Hashimoto-Kataoka Takahiro, Yasui Taku, Ikeoka Kuniyasu, Ohtani Tomohito, Sakata Yasushi, Shima Yoshihito, Kumanogoh Atsushi, Yamauchi-Takihara Keiko, Tanaka Toshio, Kishimoto Tadamitsu, Komuro Issei
  • Journal Title: International Heart Journal Volume: 54 Pages: 405-411
  • NAID: 130003383361
  • 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
• [Journal Article] Endothelial Gab1 Deletion Accelerates Angiotensin II-Dependent Vascular Inflammation and Atherosclerosis in Apolipoprotein E Knockout Mice (2012)
  • Author(s): Higuchi K
  • Journal Title: Circulation Journal Volume: 76 Issue: 8 Pages: 2031-2040
  • DOI: 10.1253/circj.CJ-11-1507
  • NAID: 10030505176
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Maximum carotid intima-media thickness improves the prediction ability of coronary artery stenosis in type 2 diabetic patients without history of coronary artery disease (2012)
  • Author(s): Irie Y, Katakami N, Kaneto H, Kasami R, Sumitsuji S, Yamasaki K, Tachibana K, Kuroda T, Sakamoto K, Umayahara Y, Ueda Y, Kosugi K, Shimomura I
  • Journal Title: Atherosclerosis Volume: 221(2) Issue: 2 Pages: 438-44
  • DOI: 10.1016/j.atherosclerosis.2012.01.022
  • Peer Reviewed
• [Journal Article] Endothelial Gab1 Deletion Accelerates Angiotensin II-dependent Vascular Inflammation and Atherosclerosis in Apolipoprotein E Knockout Mice (2012)
  • Author(s): Higuchi K, Nakaoka Y, Shioyama W, Arita Y, Hashimoto T, Yasui T, Ikeoka K, Kuroda T, Nishida K, Fujio, Y Yamauchi-Takihara K, Shirai M, Mochizuki N, Komuro I.
  • Journal Title: Circulatino Journal Volume: in press
  • NAID: 10030505176
  • Peer Reviewed
• [Journal Article] 冠動脈疾患研究の・治療の進歩と今後の課題 (2011)
  • Author(s): 中岡良和、小室一成
  • Journal Title: 日本臨床 Volume: 69(Suppl 7) Pages: 20-24
• [Journal Article] Gab1 is essential for postnatal angiogenesis via hepatocyte growth factor/c-Met signaling (2011)
  • Author(s): Shioyama W, Nakaoka Y, Higuchi K, Minami T, Taniyama Y, Nishida K, Kidoya H, Sonobe T, Naito H, Arita Y, Hashimoto T, Kuroda T, Fujio Y, Shirai M, Takakura N, Morishita R, Yamauchi-Takihara K, Kodama T, Hirano T, Mochizuki N, Komuro I
  • Journal Title: Circ Res Volume: 108 Issue: 6 Pages: 664-675
  • DOI: 10.1161/circresaha.110.232223
  • Peer Reviewed
• [Presentation] Blockade of interleukin-6 signaling prevents hypoxia induced pulmonary hypertension in mice (2013)
  • Author(s): Hashimoto-Kataoka T, Nakaoka Y, Sonobe T, Higuchi K, Arita Y, Yasui T, Ikeoka K, Masaki T, Yamauchi-Takihara K, Shirai M, Komuro I
  • Organizer: American Heart Association Scientific Sessions 2013
  • Place of Presentation: Dallas Convention Center (アメリカ合衆国・ダラス)
  • Year and Date: 2013-11-17
• [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 (2013)
  • 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)
  • Year and Date: 2013-09-27
• [Presentation] 低酸素誘発性肺高血圧モデルでIL-6/Th17細胞シグナルは肺血管リモデリングに必須である (2013)
  • Author(s): 片岡崇弘、中岡良和、曽野部崇、保仙直毅、稲垣薫克、樋口香織、有田陽、安居琢、池岡邦泰、正木豪、瀧原圭子、白井幹康、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)
  • Year and Date: 2013-09-27
• [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 (2013)
  • 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)
  • Year and Date: 2013-09-27
• [Presentation] 血管形成研究の最前線「冠静脈形成の分子機構」 (2013)
  • 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)
  • Year and Date: 2013-09-26
• [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 (2013)
  • 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)
  • Year and Date: 2013-09-06
• [Presentation] Tocilizumab Ameliorates Vascular Inflammation and Clinical Symptoms in the Patients with Takayasu Arteritis Refractory to Glucocorticoids (2013)
  • Author(s): Nakaoka Y, Arita Y, Higuchi K, Hashimoto-Kataoka T, Yasui T, Sakata Y, Yamauchi-Takihara K, Kishimoto T, Komuro I
  • 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(アメリカ合衆国・サンディエゴ)
  • Year and Date: 2013-06-29
• [Presentation] Angiopoietin-1 secreted from myocardium is essential for the formation of coronary veins in the developing heart (2013)
  • Author(s): Arita Y, Nakaoka Y, Matsunaga T, Kidoya H, Yamamizu K, Arima Y, Higuchi K, Hashimoto T, Ikeoka K, Yasui T, Nishiyama K, Kurihara H, Yamauchi-Takihara K, Yamagishi H, Takakura N, Mochizuki N, Koh GY, Komuro I
  • 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(アメリカ合衆国・サンディエゴ)
  • Year and Date: 2013-06-29
• [Presentation] Blockade of interleukin-6(IL-6) Signaling by Anti-IL-6 Monoclonal Antibody might be a Promising Therapeutic Strategy for Pulmonary Arterial Hypertension (2013)
  • Author(s): Nakaoka Y
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2013-03-16
• [Presentation] Tocilizumab Ameliorates Vascular Inflammation and Clinical Symptoms in Patients With Takayasu Arteritis Refractotry to Glucocorticoids (2013)
  • Author(s): Yoshikazu Nakaoka, Kaori Higuchi, Yoh Arita, Takahiro Kataoka, Taku Yasui, Kuniyasu Ikeoka, Tomohito Ohtani, Yasushi Sakata, Keiko Yamauchi-Takihara, Issei Komuro
  • Organizer: ACC.13
  • Place of Presentation: モスコンセンター(アメリカ合衆国・サンフランシスコ)
  • Year and Date: 2013-03-09
• [Presentation] Endothelial Gab1 deletion accelerates angiotensin II-dependent vascular inflammation and (2012)
  • Author(s): Nakaoka Y
  • Organizer: 17th International Vascular Biology Meeting 2012
  • Place of Presentation: Wiesbaden, Germany
• [Presentation] 心筋から分泌されるアンジオポイエチン1は冠静脈の形成に必須である (2011)
  • Author(s): 有田陽、中岡良和、白井学、有馬勇一郎、樋口香織、橋本崇弘、池岡邦泰、安居琢、瀧原圭子、西山功一、山岸敬幸、栗原裕基、小室一成
  • Organizer: 第2回MCC II
  • Place of Presentation: ホテルピアノ(北海道余市郡赤井川村)
  • Year and Date: 2011-09-04
• [Presentation] Gab1 is an essential component for postnatal angiogenesis after ischemia via HGF/c-Met signaling (2011)
  • Author(s): Nakaoka Y
  • Organizer: The 9th Japan-Korea Joint Symposium on Vascular Biology 2011
  • Place of Presentation: 釜山ウェスティンホテル(韓国・釜山)
  • Year and Date: 2011-08-26
  • Invited
• [Presentation] Gab1 Negatively regulates Angiotensin II-accelerated Atherosclerosis in Apolipoprotein E Deficient Mice (2011)
  • Author(s): Nakaoka Y, Higuchi K, Shioyama W, Taniyama Y, Arita Y, Hashimoto T, Fujio Y, Yamauchi-Takihara K, Morishita R, Hirano T, Komuro I
  • Organizer: 第75回日本循環器学会学術集会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2011-08-04
• [Presentation] The Role of Gab Familyl Docking Proteins in the Pathophysiology of the Cardiovascular Diseases (2011)
  • Author(s): Nakaoka Y
  • Organizer: The 12th US-Japan-Asia Dialogue on Cardiovascular Diseases and Young Investigator Competition (Pfizer)
  • Place of Presentation: 高輪プリンスホテル(東京都)
  • Year and Date: 2011-07-31
  • Invited
• [Presentation] The Role of Gab Familyl Docking Proteins in the Pathophysiology of the Cardiovascular Diseases (Keynote lecture) (2011)
  • Author(s): Nakaoka Y.
  • Organizer: The 12th US-Japan-Asia Dialogue on Cardiovascular Diseases and Young Investigator Competition(招待講演)
  • Place of Presentation: Tokyo, Japan
• [Presentation] Gab1 Negatively regulates Angiotensin II-accelerated Atherosclerosis in Apolipoprotein E Deficient Mice（FRS） (2011)
  • Author(s): Nakaoka Y, Higuchi K, Shioyama W, Arita Y, Hashimoto T, Yasui T, Ikeoka K, Kuroda T, Nishida K, Fujio, Y Yamauchi-Takihara K, Shirai M, Mochizuki N, Komuro I.
  • Organizer: 第75回 日本循環器学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜市
• [Presentation] Gab1 is an essential component for postnatal angiogenesis after ischemia via HGF/c-Met signaling (2011)
  • Author(s): Nakaoka Y.
  • Organizer: The 9th Japan-Korea Joint Symposium on Vascular Biology(招待講演)
  • Place of Presentation: Busan,Korea
• [Presentation] Endothelial Gab1Deletion Accelerates Angiotensin II-Dependent Vascular Inflammation and Atherosclerosis inApoE Knockout Mice (2011)
  • Author(s): Nakaoka Y, Higuchi K, Shioyama W, Arita Y, Hashimoto T, Yasui T, Ikeoka K, Kuroda T, Nishida K, Fujio, Y Yamauchi-Takihara K, Shirai M, Mochizuki N, Komuro I.
  • Organizer: 第28回 International Society of Heart Research 日本部会総会
  • Place of Presentation: 学術総合センター、東京都
• [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
• [Book] 血管生物医学事典(日本血管生物医学会編集、分担執筆) (2011)
  • Author(s): 小室一成・中岡良和. 他
  • Publisher: 朝倉書店
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/cardiology/27research/2751res.html
• [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制御グループ
  • URL: http://www.med.osaka-u.ac.jp/pub/cardiology/27research/2781res.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/cardiology/27research/2781res.html