Novel mechanism for the small G protein-mediated formation and maintenace of vessels

• Project/Area Number: 17K08627
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Shiga University of Medical Science
• Principal Investigator: OGITA Hisakazu 滋賀医科大学, 医学部, 教授 (50379236)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 血管 / 低分子量Gタンパク質 / 細胞接着 / 炎症 / 動脈 / 心血管疾患 / シグナル伝達 / 細胞・組織 / 循環器・高血圧

Outline of Final Research Achievements

I investigated the novel function of small G protein RhoA in vascular endothelium and smooth muscle. First, vascular endothelium- and smooth muscle-specific RhoA conditional knockout (cKO) mice were successfully generated by using the Cre-loxP system. I found that vascular endothelium-specific RhoA cKO mice were embryonic lethal due to the insufficiency of the formation of mature vasculature. On the other hand, vascular smooth muscle-specific RhoA cKO mice were born with normal external appearance. When both angiotensin II and BAPN were administered in the mice to induce vascular stress, the occurrence of aortic aneurysm was significantly high, compared with control mice. Based on these results, RhoA plays an important role in the formation and maintenance of blood vessels from the embryonic period to the adulthood.

Academic Significance and Societal Importance of the Research Achievements

動脈硬化などによる血管の障害や先天性の血管形成異常は、治療に難渋したり病態が不明なことも多い。本研究の成果は、これらの血管疾患の病態を全面的に解明する端緒となり、また、新規治療開発の基盤として活用できる。特に、超高齢社会の日本で増加している高血圧などの生活習慣病による致死的な血管病（大動脈瘤など）の新たな病態を明らかにすることができ、その対処法の道筋を示すことに貢献できた。

Research Products

• [Journal Article] Anosmin-1 activates vascular endothelial growth factor receptor and its related signaling pathway for olfactory bulb angiogenesis (2020)
  • Author(s): Matsushima Shoko、Shimizu Akio、Kondo Manami、Asano Hirotsugu、Ueno Nobuhiro、Nakayama Hironao、Sato Naoko、Komeno Masahiro、Ogita Hisakazu、Kurokawa-Seo Misuzu
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 188-188
  • DOI: 10.1038/s41598-019-57040-3
  • Peer Reviewed / Open Access
• [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome. (2020)
  • Author(s): Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 5 Pages: 6399-6417
  • DOI: 10.1096/fj.201902991r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. (2019)
  • Author(s): Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
  • Journal Title: Circulation Volume: In press Issue: 18 Pages: 2157-2169
  • DOI: 10.1161/circulationaha.118.036761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Pivotal Roles of the Epithelial Membrane Protein Family in Cancer Invasiveness and Metastasis (2019)
  • Author(s): Ahmat Amin MKB, Shimizu A, Ogita H.
  • Journal Title: Cancers Volume: 11 Issue: 11 Pages: 1620-1620
  • DOI: 10.3390/cancers11111620
  • NAID: 120006766857
  • Peer Reviewed / Open Access
• [Journal Article] Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy. (2018)
  • Author(s): Katagiri S, Iwasa M, Hayashi T, Hosono K, Yamashita T, Kuniyoshi K, Ueno S, Kondo M, Ueyama H, Ogita H, Shichida Y, Inagaki H, Kurahashi H, Kondo H, Ohji M, Hotta Y, Nakano T.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 11507-11507
  • DOI: 10.1038/s41598-018-29891-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1 (2018)
  • Author(s): Ahmat Amin MKB, Shimizu A, Zankov DP, Sato A, Kurita S, Ito M, Maeda T, Yoshida T, Sakaue T, Higashiyama S, Kawauchi A, Ogita H.
  • Journal Title: Oncogene Volume: 37 Issue: 40 Pages: 5416-5434
  • DOI: 10.1038/s41388-018-0286-0
  • Peer Reviewed / Open Access
• [Journal Article] Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma (2018)
  • Author(s): Ogura S, Yoshida Y, Kurahashi T, Egawa M, Furuta K, Kiso S, Kamada Y, Hikita H, Eguchi H, Ogita H, Doki Y, Mori M, Tatsumi T, Takehara T.
  • Journal Title: Oncotarget Volume: 9 Issue: 30 Pages: 21022-21035
  • DOI: 10.18632/oncotarget.24781
  • Peer Reviewed / Open Access
• [Journal Article] Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap (2018)
  • Author(s): Shimizu A, Zankov DP, Kurokawa-Seo M, Ogita H.
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 4 Pages: 1203-1203
  • DOI: 10.3390/ijms19041203
  • Peer Reviewed / Open Access
• [Journal Article] Critical role of dipeptidyl peptidase III in cleavage of angiotensin II and its clinical implication (2017)
  • Author(s): 清水昭男、扇田久和
  • Journal Title: 生化学 Volume: 89 Issue: 3 Pages: 449-452
  • DOI: 10.14952/SEIKAGAKU.2017.890449
  • ISSN: 0037-1017
  • Year and Date: 2017-06-25
  • Peer Reviewed / Open Access
• [Journal Article] Differential Effects of Myocardial Afadin on Pressure Overload-Induced Compensated Cardiac Hypertrophy (2017)
  • Author(s): Zankov, D.P., Sato, A., Shimizu, A., and Ogita, H.
  • Journal Title: Circulation Journal Volume: 81 Issue: 12 Pages: 1862-1870
  • DOI: 10.1253/circj.CJ-17-0394
  • NAID: 130006219260
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiological implications of dipeptidyl peptidases. (2017)
  • Author(s): Sato A, Ogita H.
  • Journal Title: Curr Protein Pept Sci Volume: - Issue: 8 Pages: 843-849
  • DOI: 10.2174/1389203718666170329104936
  • Peer Reviewed / Open Access
• [Presentation] ブルガダ症候群発症家系で見出された新たなTMEM168遺伝子変異の作用機序 (2020)
  • Author(s): 扇田久和
  • Organizer: 先端モデル動物支援プラットフォーム成果発表会
  • Invited
• [Presentation] ジペプチジルペプチダーゼ-3が糖尿病での腎機能悪化を抑制 (2019)
  • Author(s): 大東親生、清水昭男、Xiaoling Pang、扇田久和
  • Organizer: 日本生化学会近畿支部例会
• [Presentation] Dipeptidyl peptidase III によるII型糖尿病モデルマウスの心・腎臓機能低下抑制効果 (2019)
  • Author(s): 米野雅大、清水昭男、Xiaoling Pang、扇田久和
  • Organizer: 先端モデル動物支援プラットフォーム若手支援技術講習会
• [Presentation] Epithelial membrane protein 1はRac1を活性化してがん細胞の遊走を促進させがんの浸潤・転移を促進する (2019)
  • Author(s): 清水昭男、Mohammad Khusni Bin Ahmat Amin、佐藤朗、扇田久和
  • Organizer: 日本生化学会大会
• [Presentation] Novel TMEM168 gene mutation in Brugada syndrome impairs sodium channel function via the Nav1.5 degradation. (2019)
  • Author(s): 扇田久和、Dimitar P. Zankov、清水昭男
  • Organizer: American Heart Association
  • Int'l Joint Research
• [Presentation] ジペプチジルペプチダーゼ-3が糖尿病での心腎機能悪化を抑制 (2019)
  • Author(s): 清水昭男、Xiaoling Pang、扇田久和
  • Organizer: 日本血管生物医学会学術集会
• [Presentation] 冠動脈周囲脂肪組織が動脈硬化に及ぼす影響 (2019)
  • Author(s): 鈴木友彰、扇田久和、佐藤朗、木下武、高島範之、近藤康生、宮下史寛、鉢呂康平、脇坂穂高
  • Organizer: 日本冠疾患学会学術集会
• [Presentation] A novel TMEM168 gene mutation in familial Brugada syndrome attenuates Na+ channel function by modulating Nav1.5 expression. (2019)
  • Author(s): Dimitar P. Zankov、扇田久和
  • Organizer: 日本循環器学会
• [Presentation] Brugada syndrome-associated novel TMEM168 gene mutation attenuates Na+ channel function through Nav1.5 degradation. (2019)
  • Author(s): Dimitar P. Zankov、扇田久和
  • Organizer: 先端モデル動物支援プラットフォーム成果発表会
• [Presentation] VEGF-A/ニューロピリン1のシグナル伝達を阻害する細胞透過性ペプチドはがん細胞の浸潤と転移を抑制する (2018)
  • Author(s): 瀬尾美鈴、吉田亜佑美、上野信洋、パラシカー・ガルギ、早田優香、太田成美、永安良多、栃尾凌太、福光一生、中西聖磨、米倉寛人、山口淳史、浅野弘嗣、門之園哲哉、近藤科江、扇田久和、清水 昭男
  • Organizer: 日本分子生物学会年会
• [Presentation] Cardio- and reno-protective effect of dipeptidyl peptidase III. (2018)
  • Author(s): 扇田久和、Xiaoling Pang、清水昭男
  • Organizer: American Heart Association
  • Int'l Joint Research
• [Presentation] EMP1 signaling promotes cancer invasiveness and metastasis. (2018)
  • Author(s): Mohammad Khusni Bin Ahmat Amin、清水昭男、Dimitar P. Zankov、佐藤朗、扇田久和
  • Organizer: 日本癌学会学術総会
• [Presentation] Novel therapeutic role for dipeptidyl peptidase III in the treatment of diabetic nephropathy. (2018)
  • Author(s): Xiaoling Pang、清水昭男、Dimitar P. Zankov、佐藤朗、石田哲夫、扇田久和
  • Organizer: 日本生化学会大会
• [Presentation] 新たな遺伝子変異が病因と考えられた日本人青錐体1色覚（BCM）の症例 (2018)
  • Author(s): 岩佐真紀、上山久雄、片桐聡、林孝彰、山下高廣、七田芳則、大路正人、扇田久和
  • Organizer: 日本生化学会大会
• [Presentation] Protective role of intercalated disk protein afadin in the pressure-overloaded heart. (2018)
  • Author(s): 扇田久和
  • Organizer: 日本循環器学会基礎研究フォーラム
  • Invited
• [Presentation] Identification and arrhythmogenic significance of a novel TMEM168 mutation in Brugada syndrome. (2018)
  • Author(s): Dimitar P. Zankov、扇田久和
  • Organizer: 日本循環器学会基礎研究フォーラム
• [Presentation] 糖尿病性腎症に対するジペプチジルペプチダーゼIIIの保護作用 (2018)
  • Author(s): 山口侑汰、清水昭男、Xiaoling Pang、Dimitar P. Zankov、石田哲夫、扇田久和
  • Organizer: 日本生化学会近畿支部例会
• [Presentation] Critical role of intercalated disk protein afadin in cardiac protection against chronic pressure overload-induced heart failure. (2018)
  • Author(s): 扇田久和
  • Organizer: 日本循環器学会（シンポジウム）
• [Presentation] Intercalated disk protein afadin prevents pressure overload-induced cardiac dysfunction in a stimulus-dependent manner. (2018)
  • Author(s): Dimitar P. Zankov、扇田久和
  • Organizer: 日本循環器学会
• [Presentation] Exome-wide analysis links nuclear membrane protein TMEM168 to the arrhythmogenesis in a family with inherited Brugada syndrome. (2018)
  • Author(s): Dimitar P. Zankov、扇田久和
  • Organizer: 先端モデル動物支援プラットフォーム成果発表会
• [Presentation] Essential role of myocardial afadin in cardiac protecting during chronic pressure overload. (2018)
  • Author(s): Dimitar P. Zankov、扇田久和
  • Organizer: 日本循環器学会基礎研究フォーラム
• [Presentation] Deciphering signaling pathway of a novel cancer pro-invasive and -metastatic molecule, epithelial membrane protein 1. (2017)
  • Author(s): Mohammad Khusni B. Ahamad Amin、清水昭男、Dimitar P. Zankov、佐藤朗、扇田久和
  • Organizer: 生命科学系学会合同年次集会
• [Presentation] Myocardial afadin is essential for maintaining cardiac function against mechanical stress-induced, but not pharmacological stimulation-mediated, pressure overload. (2017)
  • Author(s): Hisakazu Ogita, Dimitar P. Zankov
  • Organizer: American Heart Association
  • Int'l Joint Research
• [Presentation] Critical role of myocardial afadin in cardiac protection during chronic mechanical overload. (2017)
  • Author(s): Dimitar P. Zankov、清水昭男、佐藤朗、扇田久和
  • Organizer: 日本生化学会近畿支部例会
• [Presentation] ペプチド分解酵素DPP IIIの降圧作用と新規高血圧治療としての有用性 (2017)
  • Author(s): 扇田久和
  • Organizer: 臨床高血圧フォーラム（シンポジウム）
  • Invited
• [Remarks] 滋賀医科大学・分子病態生化学部門
  • URL: http://www.shiga-med.ac.jp/~hqbioch2/
• [Remarks] 滋賀医科大学分子病態生化学
  • URL: http://www.shiga-med.ac.jp/~hqbioch2/
• [Patent(Industrial Property Rights)] 心不全非ヒト霊長類モデル動物の製造方法 (2019)
  • Inventor(s): 扇田久和、佐藤朗
  • Industrial Property Rights Holder: 扇田久和、佐藤朗
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-125286
  • Filing Date: 2019