大動脈瘤の新規治療薬の開発

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25670131
• Research Institution: Yokohama City University
• Principal Investigator: 石川 義弘 横浜市立大学, 医学(系)研究科(研究院), 教授 (40305470)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 薬理学 / 循環器・高血圧 / シグナル伝達 / 病理学 / 外科

Outline of Annual Research Achievements

脂質異常症や高血圧、心不全に対する画期的な薬剤が次々と開発される中、大動脈瘤は数少ない未開発領域である。炎症性疾患や動脈硬化により動脈壁の脆弱化が進み、大血管が拡張あるいは壁解離が進行すると大動脈瘤を生ずる。大動脈瘤は加齢とともに進行するが、動脈瘤の治療は外科的な手術のみであり、進展を抑える薬理学的治療法はない。我々は血管リモデリングの研究を通じて、大動脈瘤にはプロスタグランジン受容体を通じた弾性線維の制御メカニズムが存在すること、さらに大動脈瘤の進展を抑制する薬物療法を見出した。本申請ではこの分子メカニズムの解明を進め、臨床応用が可能な大動脈瘤の治療薬を開発し、高齢化社会における先進医療の基盤確立を目指した。
二年間にわたる萌芽研究において、現在では治療あるいは予防困難と考えられている大動脈瘤に対して、経口薬を投与することによって、進展の悪化が防止可能であるのかの検討を終了した。これまでの他の研究者の報告によっても、大動脈瘤の悪化には周辺組織における炎症の存在が不可欠である。そこで炎症ホルモンであるプロスタグランジンの拮抗剤を投与することによって、局所の炎症を抑え、大動脈瘤の進行を抑えることができるかを検討した。動物実験や器官培養実験結果から、経口剤による炎症の低下、さらに大動脈瘤の発症を抑えることが可能である結果が得られた。
これはこれまで治療法のなかった大動脈瘤の患者に対して、安全かつ安心の医療を提供する可能性を意味する。

Research Products

• [Journal Article] Oscillation of cAMP and Ca2+ in cardiac myocytes. (2015)
  • Author(s): Kamide T, Okumura S, Ghosh S, Shinoda Y, Mototani Y, Ohnuki Y, Jin H, Cai W, Suita K, Sato I, Umemura M, Fujita T, Yokoyama U, Sato M, Frutani K, Kitano H, and Ishikawa Y.
  • Journal Title: J. Physiol. Sci. Volume: 65 Pages: 195-200
  • DOI: 10.1007/s12576-014-0354-3.
  • Peer Reviewed
• [Journal Article] Coupling of beta1-adrenergic receptor to type 5 adenylyl cyclase and its physiological relevance in cardiac myocytes. (2015)
  • Author(s): Tsunematsu T, Okumura S, Mototani Y, Ohnuki Y, Jin H, Cai W, SuitaK, Sato I, Umemura M, Yokoyama U, Sato M, Fujita T, and Ishikawa Y.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 458 Pages: 531-535
  • DOI: 10.1016/j.bbrc.2015.01.149.
  • Peer Reviewed
• [Journal Article] A magnetic anti-cancer compound for magnet-guided delivery and magnetic resonance imaging. (2015)
  • Author(s): Eguchi H, Umemura M, Kurotani R, Fukumura H, Sato I, Kim J-H, Hoshino Y, Lee J, Amemiya N, Sato M, Hirata K, Sigh DJ, Masuda T, Yamamoto M, Urano T, Yoshida K, Tanigaki K, Yamamoto M, Sato M, Inoue S, Aoki I and Ishikawa Y.
  • Journal Title: Sci. Rep. Volume: 5 Pages: 9194
  • DOI: 10.1038/srep09194.
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 inhibits elastogenesis in the ductus arteriosus via EP4 signaling. (2014)
  • Author(s): Yokoyama U, Minamisawa S, Shioda A, Ishiwata R, Jin MH, Masuda M, Asou T, Sugimoto Y, Aoki H, Nakamura T, and Ishikawa Y
  • Journal Title: Circulation. Volume: 129 Pages: 487-496
  • DOI: 10.1161/CIRCULATIONAHA.113.004726.
  • Peer Reviewed
• [Journal Article] Store-operated Ca2+ entry (SOCE) Regulates Melanoma Proliferation and Cell Migration. (2014)
  • Author(s): Umemura M, Baljinnyam E, Feske S, De Lorenzo MS, Xie LH, Feng X, Oda K, Makino A, Fujita T, Yokoyama U, Iwatsubo M, Chen S, Goydos JS, Ishikawa Y, and Iwatsubo K
  • Journal Title: PloS One. Volume: 9 Pages: e89292
  • DOI: 10.1371/journal.pone.0089292.
  • Peer Reviewed
• [Journal Article] Hyperthermia generated with ferucarbotran (Resovist®) in an alternating magnetic field enhances cisplatin-induced apoptosis of cultured human oral cancer cells (2014)
  • Author(s): Sato I, Umemura M, Mitsudo K, Kioi M, Nakashima H, Iwai T, Feng X, Oda K, Miyajima A, Makino A, Iwai M, Fujita T, Yokoyama U, Okumura S, Sato M, Eguchi H, Tohnai I, Ishikawa Y.
  • Journal Title: J Physiol Sci. Volume: 64 Pages: 177-183
  • DOI: 10.1007/s12576-014-0309-8.
  • Peer Reviewed
• [Journal Article] Decreased serum osmolality promotes ductus arteriosus constriction. (2014)
  • Author(s): Aoki R, Yokoyama U, Ichikawa Y, Taguri M, Kumagaya S, Ishiwata R, Yanai C, Fujita S, Umemura M, Fujita T, Okumura S, Sato M, Minamisawa S, Asou T, Masuda M, Iwasaki S, Nishimaki S, Seki K, Yokota S, and Ishikawa Y
  • Journal Title: Cardiovasc. Res Volume: 104 Pages: 326-336
  • DOI: 10.1093/cvr/cvu199.
  • Peer Reviewed
• [Journal Article] Three-dimensional multilayers of smooth muscle cells as a new experimental model for vascular elastic fiber formation studies. (2014)
  • Author(s): Ishiwata R, Yokoyama U, Matsusaki M, Asano Y, Kadowaki K, Ichikawa Y, Umemura M, Fujita T, Minamisawa S, Shimoda H, Akashi M, and Ishikawa Y
  • Journal Title: Atherosclerosis. Volume: 233 Pages: 590-600
  • DOI: 10.1016/j.atherosclerosis.2014.01.045.
  • Peer Reviewed
• [Journal Article] Protection of cardiomyocytes from the hypoxia-mediated injury by a Peptide targeting the activator of g-protein signaling 8. (2014)
  • Author(s): Sato M, Hiraoka M, Suzuki H, Sakima M, Mamun AA, Yamane Y, Fujita T, Yokoyama U, Okumura S, Ishikawa Y
  • Journal Title: PLoS One. Volume: 9 Pages: e91980
  • DOI: 10.1371/journal.pone.0091980.
  • Peer Reviewed
• [Journal Article] Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses. (2014)
  • Author(s): Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Kurotani R, Suita K, Kawakami Y, Hamaguchi S, Abe T, Kiyonari H, Tsunematsu T, Bai Y, Suzuki S, Hidaka Y, Umemura M, Ichikawa Y, Yokoyama U, Sato M, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, and Ishikawa Y
  • Journal Title: J Clin Invest. Volume: 124 Pages: 2785-2801
  • DOI: 10.1172/JCI64784.
  • Peer Reviewed
• [Journal Article] Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3. (2014)
  • Author(s): Tsutsumi YM, Tsutsumi R, Hamaguchi E, Sakai Y, Kasai A, Ishikawa Y, Yokoyama U, and Tanaka K.
  • Journal Title: Cardiovasc Diabetol. Volume: 13 Pages: 132
  • DOI: 10.1186/s12933-014-0132-9.
  • Peer Reviewed
• [Journal Article] Geranylgeranylacetone protects the heart via caveolae and caveolin-3. (2014)
  • Author(s): Tsutsumi YM, Tsutsumi R, Hirokawa YT, Sakai Y, Hamaguchi E, Ishikawa Y, Yokoyama U, Kasai A, Kambe N, and Tanaka K.
  • Journal Title: Life Sciences. Volume: 101 Pages: 43-48
  • DOI: 10.1016/j.lfs.2014.02.019. Epub 2014 Feb 26.
  • Peer Reviewed
• [Journal Article] Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling. (2014)
  • Author(s): Baljinnyam E, Umemura M, Chuang C, De Lorenzo M, Iwatsubo M, Chen S, Goydos J, Ishikawa Y, Whitelock J, and Iwatsubo K
  • Journal Title: Pigment Cell & Melanoma Research. Volume: 27 Pages: 611-620
  • DOI: 10.1111/pcmr.12250.
  • Peer Reviewed
• [Journal Article] A Case of R-II-B Type Single Coronary Artery Evaluated by Multi-Detector Computed Tomography and Coronary Angiography. (2014)
  • Author(s): Narikawa M, Kiyokuni M, Umemura M, Kawashima C, Doi H, Hisa A, Tomari S, Mitsuhashi T, Ishikawa Y and Endo T.
  • Journal Title: J Clin Exp Cardiolog, Volume: 5 Pages: 10
  • Peer Reviewed
• [Journal Article] Impaired NO Production and Increased Blood Pressure in Systemic Heterozygous ATP2B1 Null Mice. (2014)
  • Author(s): Fujiwara A, Hirawa N, Fujita M, Kobayashi Y, Okuyama Y, Yatsu K, Katsumata M, Yamamoto Y, Ichihara N, Saka S, Toya Y, Yasuda G, Tabara Y, Miki T, Ueshima H, Ishikawa Y, and Umemura S.
  • Journal Title: J Hypertension. Volume: 32 Pages: 1415-1423
  • DOI: 10.1097/HJH.0000000000000206.PMID:24805951
  • Peer Reviewed
• [Journal Article] Deletion of the angiotensin II type 1 receptor-associated protein enhances renal sodium reabsorption and exacerbates angiotensin II-mediated hypertension. (2014)
  • Author(s): Ohsawa M, Tamura K, Wakui H, Maeda A, Dejima T, Kanaoka T, Azushima K, Uneda K, Tsurumi-Ikeya Y, Kobayashi R, Matsuda M, Uchida S, Toya Y, Kobori H, Nishiyama A, Yamashita A, Ishikawa Y, and Umemura S.
  • Journal Title: Kidney International. Volume: 86 Pages: 570-581
  • DOI: 10.1038/ki.2014.95.
  • Peer Reviewed
• [Journal Article] Role of Cyclic AMP Sensor Epac1 in Masseter Muscle Hypertrophy and Myosin Heavy Chain Transition Induced by 2-Adrenoceptor Stimulation. (2014)
  • Author(s): Ohnuki Y, Umeki D, Mototani Y, Jin H, Cai W, Shiozawa K, Suita K, Saeki Y, Fujita T, Ishikawa Y, and Okumura S.
  • Journal Title: J. Physiol. Volume: 592 Pages: 5461-5475
  • DOI: 10.1113/jphysiol.2014.282996.
  • Peer Reviewed
• [Journal Article] Obstructive Sleep Apnea and Hypertension:A New Way to Go. (2014)
  • Author(s): Ishikawa Y.
  • Journal Title: J Sleep Disorders Ther. Volume: 3 Pages: 4
  • Peer Reviewed
• [Presentation] Cardiac overexpression of Translationally Controlled Tumor Protein (TCTP) prevents the development of Dihydroartemisinin (DHA)-induced heart. (2015)
  • Author(s): Cai W, Fujita T, Hidaka Y, Jin H, Hasegawa N, Ishikawa Y
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル大阪、堂島リバーフォーラム、ＡＢＣホール(大阪府）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Transient receptor potential cation channel 3 (TRPC3) regulates tumor proliferation and migration of BRAF wild type human malignant melanoma. (2015)
  • Author(s): Oda K, Umemura M, Baljinntam E, Yamaguchi Y, Aihara M, Iwatsubo K, Ishikawa Y.
  • Organizer: The 106th American Association for Cancer Research Annual meeting.
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] Methotrexate derivative with intrinsic magnetism. (2015)
  • Author(s): Umemura M, Katsumata M, Sato I, Nagasako A, Aoyama H, Makino A, Ohatake M, Oda K, Eguchi H, Ishikawa Y.
  • Organizer: The 106th American Association for Cancer Research Annual meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] Simultaneous hyperthermic-chemotherapy for glioblastoma using a single anti-cancer compound with magnetism. (2015)
  • Author(s): Ohtake M, Umemura M, Sato I, Oda K, Nagasako A, Makino A, Aoyama H, Katsumata M, Eguchi H, Kawahara N , Ishikawa Y
  • Organizer: The 106th American Association for Cancer Research Annual meeting.
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] A novel methotrexate derivative with intrinsic magnetism. (2015)
  • Author(s): Katsumata M, Umemura M, Sato I, Ohtake M, Oda K, Nagasako A, Makino A, Aoyama H, Eguchi H, Ishikawa Y.
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県）
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Magnetized paclitaxel derivative for novel triple negative breast cancer therapy. (2015)
  • Author(s): Makino A, Umemura M, Sato I, Katsumata M, Nagasako A, Oda K, Ohtake M, Aoyama H, Eguchi H, Ishikawa Y.
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県）
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] A novel methotrexate derivative with intrinsic magnetism. (2015)
  • Author(s): Katsumata M, Umemura M, Sato I, Ohtake M, Oda K, Nagasako A, Makino A, Aoyama H, Eguchi H, Ishikawa Y.
  • Organizer: 第88回日本薬理学会
  • Place of Presentation: 名古屋国際会議場（愛知県）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] プロスタグランディンE－EP4はfibulin-1を介して生理的・病的血管内膜肥厚の形成に関与する． (2014)
  • Author(s): 矢内千春, 横山詩子, 熊谷 駿, 手島隆之, 佐藤綾美, 石川義弘
  • Organizer: 第13回日本心臓血管発生研究会
  • Place of Presentation: 磐梯熱海温泉 ホテル 華の湯(福島県）
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] 抗ヘルペス薬による心房細動抑制． (2014)
  • Author(s): 吹田憲治, 藤田孝之, 奥村 敏, 石川義弘
  • Organizer: 第131回日本薬理学会関東部会
  • Place of Presentation: 横浜市立大学医学部ﾍﾎﾞﾝﾎｰﾙ（神奈川県）
  • Year and Date: 2014-10-11 – 2014-10-11
• [Presentation] A novel paclitaxel with intrinsic magnetism. (2014)
  • Author(s): Makino A, Umemura M, Sato I, Oda K, Otake M, Nagasako A, Eguchi H, Ishikawa Y.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Development of combination therapy with cisplatin and hyperthermia generated with ferucarbotran (Resovist) in an alternating magnetic field for oral cancer. (2014)
  • Author(s): Sato I, Mitsudo K, Umemura M, Nakashima H, Kioi M, Eguchi H, Ishikawa Y,Tohnai.I
  • Organizer: The 6th Asian Congress of Hyperthermic Oncology (ACHO)
  • Place of Presentation: 福井県民ホール、福井市地域交流プラザ（福井県）
  • Year and Date: 2014-09-05 – 2014-09-06
• [Presentation] EPAC1 plays an important role in regulation of renin and AQP2 expression in the kidney of mice. (2014)
  • Author(s): Jin H, Fujita T, Cai W, Hidaka Y, Sagara S, Kubota K, Suita K, Ishikawa Y.
  • Organizer: European Society of Cardiorogy Congress.
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Prostaglandin E2-EP4 plays a protective role against cardiac fibrosis. (2014)
  • Author(s): Ishiwata R, Yokoyama U, Inoue S, Ichikawa Y, Ishikawa Y.
  • Organizer: European Society of Cardiorogy Congress.
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Cardiac overexpression ofure. Chronic Treatment with Dihydroartemisinin, a TCTP Down-regulating Agent, Results in Cardiac Dysfunction in Mice． (2014)
  • Author(s): Cai W, Fujita T, Hidaka Y, Jin H, K. Sagara S, Kubota K, Suita K, Ishikawa Y.
  • Organizer: European Society of Cardiorogy Congress.
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced atrial fibrillation in mice. (2014)
  • Author(s): Suita K, Fujita T, Cai W, Hidaka Y, Jin H, Jin M, Okumura S, Ishikawa Y.
  • Organizer: European Society of Cardiorogy Congress.
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] 体液量調節におけるEPAC1の役割についての検討. (2014)
  • Author(s): Jin H, Fujita T, Cai W, Hidaka Y, Sagara S, Suita K, Ishikawa Y
  • Organizer: 第５７会日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] ヒト大動脈瘤組織におけるPGE2-EP4誘導性分泌タンパク質の網羅的解析. (2014)
  • Author(s): 石渡 遼, 横山詩子, 荒川憲昭, 安田章沢, 郷田素彦, 鈴木伸一, 益田宗孝, 石川義弘
  • Organizer: 第35回日本循環制医学会総会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県）
  • Year and Date: 2014-07-04 – 2014-07-05
• [Presentation] 心臓型アデニル酸シクラーゼの選択的阻害剤ビダラビンによる心房細動抑制. (2014)
  • Author(s): 吹田憲治, 藤田孝之, 蔡 文倩, 金 慧玲, 奥村 敏, 石川義弘
  • Organizer: 第35回日本循環制御医学会総会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県）
  • Year and Date: 2014-07-04 – 2014-07-05
• [Presentation] MRI造影剤フェルカルボトランを用いた新しい温熱化学療法の開発. (2014)
  • Author(s): 佐藤 格, 光藤健司, 梅村将就, 宮島章嘉, 中島英行, 來生 知, 石川義弘, 藤内 祝.
  • Organizer: 第38回日本頭頚部癌学会
  • Place of Presentation: 東京ファッションタウンビルホール（東京都）
  • Year and Date: 2014-06-12 – 2014-06-13
• [Presentation] Nuclear Factor kappa B Inhibition Promotes Closure of the Rat Ductus Arteriosus. (2014)
  • Author(s): Kajimura I, Yokoyama U, Ishikawa Y, Minamisawa S.
  • Organizer: Experimental Biology Annual Meeting.
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-04-26 – 2014-04-30
• [Presentation] Prostaglandin E2 receptor EP4 signaling in vascular smooth muscle cells decreases aortic elasticity. (2014)
  • Author(s): Ichikawa Y, Yokoyama U, Ishikawa Y.
  • Organizer: Experimental Biology Annual Meeting.
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-04-26 – 2014-04-30
• [Presentation] Development of thermochemotherapy using cisplatin and ferucarbotran (Resovist®) in head and neck cancer. (2014)
  • Author(s): Sato I, Umemura M, Mitsudo K, Feng X, Nakashima H, Kioi M, Eguchi H, Tohnai I, Ishikawa Y
  • Organizer: The 105th American Association for Cancer Research Annual meeting.
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] A novel treatment for triple-negative breast cancer using intrinsic magnetized paclitaxel. (2014)
  • Author(s): Umemura M, Makino A, Sato I, Feng X, Iwai M, Oda K, Miyajima A, Otake M, Nagasako A, Matsuo K, Eguchi H, and Ishikawa Y.
  • Organizer: The 105th American Association for Cancer Research Annual meeting.
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Book] 標準生理学 第8版 第29章「赤血球」 (2014)
  • Author(s): 石川義弘
  • Total Pages: 1140
  • Publisher: 医学書院
• [Book] 標準生理学 第8版 第39章 「局所循環」 (2014)
  • Author(s): 石川義弘
  • Total Pages: 1140
  • Publisher: 医学書院
• [Remarks] 横浜市立大学大学院医学研究科 循環制御医学 ホームページ
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/index.html
• [Patent(Industrial Property Rights)] グルタミン酸による動脈管開存症の予防又は治療 (2015)
  • Inventor(s): 横山詩子、石川義弘、藤田秀次郎
  • Industrial Property Rights Holder: 公立大学法人横浜市立大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: PCT/JP/2015/054277
  • Filing Date: 2015-02-17
  • Overseas
• [Patent(Industrial Property Rights)] 三次元細胞集合体の作製方法 (2015)
  • Inventor(s): 横山詩子、石川義弘、金子真、佐久間臣耶、新井史人
  • Industrial Property Rights Holder: 横浜市立大学、大阪大学、名古屋大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2015-033064
  • Filing Date: 2015-02-23
• [Patent(Industrial Property Rights)] 三次元組織体及びその製造方法 (2014)
  • Inventor(s): 横山詩子、石川義弘、明石満、松崎典弥
  • Industrial Property Rights Holder: 公立大学法人横浜市立大学、国立大学法人大阪大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: PCT/JP2014/77083
  • Filing Date: 2014-10-09
  • Overseas