Development of novel aortic dissection model based on vascular endothelial dysfunction and elucidation of pathophysiological mechanisms

• Project/Area Number: 15K07967
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: The University of Tokushima
• Principal Investigator: ISHIZAWA Keisuke 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (60398013)
• Co-Investigator(Kenkyū-buntansha): 石澤 有紀 徳島大学, 大学院医歯薬学研究部(医学系), 講師 (40610192)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 動脈硬化 / 大動脈解離 / 血管内皮

Outline of Final Research Achievements

In the present study, we have succeeded to establish a novel acute aortic dissection model mouse. Aortic dissection in C57Bl/6J mouse is induced by the combined usage of Nω-nitro-L-arginine methyl ester (L-NAME), angiotensin II (Ang II), and β-aminopropionitrile (BAPN). L-NAME induces endothelial cell damage. Administration of Ang II elevated systolic blood pressure. BAPN is one of the lysyloxidase inhibitor, which causes vessel medial fragility. We named this model “LAB” model. Pitavastatin, an HMG-CoA inhibitor used as lipid lowering agent, suppressed the incidence of aortic dissection. From the results of in vitro analysis using cultured human umbilical vein endothelial cells, pitavastatin effects are mediated by extracellular signal-regulated kinase 5 (ERK5) activation. Our findings suggested that this novel “LAB” model are useful to examine the pathophysiology of aortic dissection and the estimation of the drug efficacy against aortic dissection.

Research Products

• [Journal Article] Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice (2017)
  • Author(s): Yasumasa Ikeda, Yuya Horinouchi, Hirofumi Hamano, Tasuku Hirayama, Seiji Kishi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Ken-ichi Aihara, Hideko Nagasawa, Koichiro Tsuchiya, and Toshiaki Tamaki
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 10621-10621
  • DOI: 10.1038/s41598-017-11089-0
  • NAID: 120006534998
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacological approach for drug repositioning against cardiorenal diseases (2017)
  • Author(s): Zamami Y, Imanishi M, Takechi K, Ishizawa K
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 3.4 Pages: 197-201
  • DOI: 10.2152/jmi.64.197
  • NAID: 130006105190
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest. (2017)
  • Author(s): 48)Niimura T, Zamami Y, Koyama T, Izawa-Ishizawa Y, Miyake M, Koga T, Harada K, Ohshima A, Imai T, Kondo Y, Imanishi M, Takechi K, Fukushima K, Horinouchi Y, Ikeda Y, Fujino H, Tsuchiya K, Tamaki T, Hinotsu S, Kano MR, Ishizawa K.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 17919-17919
  • DOI: 10.1038/s41598-017-17686-3
  • NAID: 120006535027
  • Peer Reviewed / Open Access
• [Journal Article] Iron-induced skeletal muscle atrophy involves an Akt-forkhead box O3-E3 ubiquitin ligase-dependent pathway. (2016)
  • Author(s): Yasumasa Ikeda, Mizuki Imao, Akiho Satoh, Hiroaki Watanabe, Hirofumi Hamano, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Licht Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
  • Journal Title: Journal of Trace Elements in Medicine and Biology Volume: 35 Pages: 66-76
  • DOI: 10.1016/j.jtemb.2016.01.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical Evaluation of Pharmacist Interventions in Patients Treated with Anti-methicillin-Resistant <i>Staphylococcus aureus</i> Agents in a Hematological Ward (2016)
  • Author(s): Naoto Okada, Shuji Fushitani, Momoyo Azuma, Shingen Nakamura, Toshimi Nakamura, Kazuhiko Teraoka, Hiroyoshi Watanabe, Masahiro Abe, Kazuyoshi Kawazoe, Keisuke Ishizawa
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 39 Issue: 2 Pages: 295-300
  • DOI: 10.1248/bpb.b15-00774
  • NAID: 130005122366
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice (2015)
  • Author(s): Soichiro Tajima, Yasumasa Ikeda, Hideaki Enomoto, Imao Mizuki, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Rihito Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Journal Title: European Journal of Nutrition Volume: 印刷中 Issue: 5 Pages: 709-719
  • DOI: 10.1007/s00394-014-0749-1
  • NAID: 120006732013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spontaneously hyperactive MEK-Erk pathway mediates paradoxical facilitation of cell proliferation in mild hypoxia. (2015)
  • Author(s): Miyamoto L, Yagi Y, Hatano A, Kawazoe K, Ishizawa K, Minakuchi K, Tomita S, Tsuchiya K.
  • Journal Title: Biochim Biophys Acta Volume: 1850 Issue: 4 Pages: 640-646
  • DOI: 10.1016/j.bbagen.2014.12.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Long-Term High-Fat Diet Changes Iron Distribution in the Body, Increasing Iron Accumulation Specifically in the Mouse Spleen (2015)
  • Author(s): Noriko Yamano, Yasumasa Ikeda, Minoru Sakama, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Licht Miyamoto, Shuhei Tomita, Koichiro Tsuchiya, Toshiaki Tamaki
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 61 Issue: 1 Pages: 20-27
  • DOI: 10.3177/jnsv.61.20
  • NAID: 130005070829
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characteristics and risk factors of interstitial lung disease induced by chemotherapy for lung cancer (2015)
  • Author(s): Takumi Sakurada, Soji Kakiuchi, Soichiro Tajima, Yuya Horinouchi, Naoto Okada, Hirotaka Nishisako, Toshimi Nakamura, Kazuhiko Teraoka, Kazuyoshi Kawazoe, Hiroaki Yanagawa, Yasuhiko Nishioka, Kazuo Minakuchi, Keisuke Ishizawa
  • Journal Title: The Annals Pharmacotherapy Volume: 49(4) Issue: 4 Pages: 398-404
  • DOI: 10.1177/1060028014566446
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia Decreases Glucagon-Like Peptide-1 Secretion from the GLUTag Cell Line (2015)
  • Author(s): Yoshitaka Kihira, Ariunzaya Burentogtokh, Mari Itoh, Yuki Izawa-Ishizawa, Keisuke Ishizawa, Yasumasa Ikeda, Koichiro Tsuchiya, and Toshiaki Tamaki
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 38 Issue: 4 Pages: 514-521
  • DOI: 10.1248/bpb.b14-00612
  • NAID: 130005062264
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Bilirubin exerts pro-angiogenic effects through an Akt-eNOS-dependent pathway (2015)
  • Author(s): Yasumasa Ikeda, Hamano Hirofumi, Satoh Akiho, Horinouchi Yuya, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Ken-ichi Aihara, Koichiro Tsuchiya and Toshiaki Tamaki
  • Journal Title: Hypertension Research Volume: 38(11) Issue: 11 Pages: 733-740
  • DOI: 10.1038/hr.2015.74
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ephedra protects vascular endothelium cells from vinorelbine-induced cytotoxicity by preserving endothelial nitric oxide synthase activity (2015)
  • Author(s): Ken Konaka, Kouta Moriyama, Naoto Okada, Takahiro Nishisako, Masayuki Syono, Kazuyoshi Kawazoe, Keisuke Ishizawa
  • Journal Title: Traditional & Kampo Medicine Volume: 2 Issue: 2 Pages: 274-280
  • DOI: 10.1002/tkm2.1024
  • Peer Reviewed / Open Access
• [Journal Article] Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids (2015)
  • Author(s): Takumi Sakurada, Soji Kakiuchi, Soichiro Tajima, Yuya Horinouchi, Ken Konaka, Naoto Okada, Hirotaka Nishisako, Toshimi Nakamura, Kazuhiko Teraoka, Kazuyoshi Kawazoe, Hiroaki Yanagawa, Yasuhiko Nishioka, Keisuke Ishizawa
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 38 Issue: 11 Pages: 1752-1756
  • DOI: 10.1248/bpb.b15-00435
  • NAID: 130005106388
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Japanese Physicians' Views on Drug Post-Marketing Surveillance (2015)
  • Author(s): Kazuki Maeda, Rumi Katashima, Keisuke Ishizawa, Hiroaki Yanagawa
  • Journal Title: J Clin Med Res Volume: 7 Issue: 12 Pages: 956-960
  • DOI: 10.14740/jocmr2328w
  • Peer Reviewed / Open Access
• [Presentation] フェブキソスタットはアンジオテンシンII誘発性大動脈線維化を抑制する (2017)
  • Author(s): 今西正樹、田中恭平、生藤来希、座間味 義人、武智研志、堀ノ内裕也、 石澤有紀、池田康将、藤野裕道、土屋浩一郎、玉置俊晃、石澤啓介
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2017-03-15
  • Int'l Joint Research
• [Presentation] Angiotensin II誘発性血管リモデリングに対するfebuxostatの効果 (2017)
  • Author(s): 今西正樹、田中恭平、生藤来希、座間味義人、武智研志、堀ノ内裕也、 石澤有紀、池田康将、藤野裕道、土屋浩一郎、玉置俊晃、石澤啓介
  • Organizer: 第46回日本心脈管作動物質学会
  • Place of Presentation: 琉球大学（沖縄県中頭郡）
  • Year and Date: 2017-02-10
  • Int'l Joint Research
• [Presentation] インドキシル硫酸はヘプシジンを介した鉄代謝異常に関与する (2017)
  • Author(s): 濱野裕章、池田康将、渡邉大晃、堀ノ内裕也、石澤有紀、石澤啓介、土屋浩一郎、玉置俊晃
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] The effects of febuxostat on angiotensin II-induced vascular remodeling (2017)
  • Author(s): Masaki Imanishi, Kyohei Tanaka, Raiki Ikuto, Yoshito Zamami, Kenshi Takechi, Yuya Horinouchi, Yuki Ishizawa, Yasumasa Ikeda, Hiromichi Fujino, Koichiro Tsuchiya, Toshiaki Tamaki, Keisuke Ishizawa
  • Organizer: European Meeting of Hypertension and Cardiovascular Protection
  • Int'l Joint Research
• [Presentation] 急性大動脈解離易発症マウスにおけるquercetinの効果 (2017)
  • Author(s): 鍵本優有、石澤有紀、細岡真由子、斎藤尚子、鈴木琴子、今西正樹、 堀ノ内裕也、座間味義人、武智研志、池田康将、土屋浩一郎、玉置俊晃、 石澤啓介
  • Organizer: 第56回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会
• [Presentation] Indoxyl Sulfate Disturbs Normal Iron Metabolism via Hepcidin Upregulation in Chronic Kidney Disease (2017)
  • Author(s): Hirofumi Hamano, Yasumasa Ikeda, Hiroaki Watanabe, Yuya Horinouchi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Organizer: ASN Kidney Week 2017 Annual Meeting
  • Int'l Joint Research
• [Presentation] ケルセチンによる動脈硬化性疾患発症に対する予防効果の検討 (2017)
  • Author(s): 石澤有紀、鍵本優有、今西正樹、堀ノ内裕也、鈴木琴子、岩田悠佑、座間味義人、武智研志、池田康将、玉置俊晃、石澤啓介
  • Organizer: 第27回日本循環薬理学会
• [Presentation] Topical Application of Nitrosonifedipine, a Novel Free Radical Scavenger, Ameliorate the Ischemic Skin Flap Necrosis (2016)
  • Author(s): Yutaka Fukunaga, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Yasumasa Ikeda, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki, Ichiro Hashimoto
  • Organizer: Plastic Surgery THE MEETING 2016
  • Place of Presentation: ロサンゼルス（アメリカ）
  • Year and Date: 2016-09-23
  • Int'l Joint Research
• [Presentation] 脳卒中後の神経症状増悪に対するニトロソニフェジピンの効果 (2016)
  • Author(s): 今西 正樹, 石澤 有紀, 座間味 義人, 田淵 正樹, 玉置 俊晃, 石澤 啓介
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: ソウル（韓国）
  • Year and Date: 2016-07-02
  • Int'l Joint Research
• [Presentation] The effects of pitavastatin, a lipid-lowering agent, against aortic dissection model mice induced by L-NAME, a nitric oxide synthase inhibitor (2016)
  • Author(s): Yuki Izawa-Ishizawa, Masaki Imanishi, Yuya Horinouchi, Kenshi Takechi, Yoshito Zamami, Yasumasa Ikeda, Koichiro Tsuchiya, Toshiaki Tamaki, Keisuke Ishizawa
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] The Involvement of Iron Supplementation on Erythropoietin Expression (2016)
  • Author(s): Yasumasa Ikeda, Keisuke Oshima, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Organizer: Experimental Biology 2016
  • Place of Presentation: サンディエゴ（アメリカ）
  • Year and Date: 2016-04-02
  • Int'l Joint Research
• [Presentation] 無機リン刺激による血管平滑筋細胞石灰化におけるrho-kinase 及び cyclophilinA の関与 (2016)
  • Author(s): 鍵本 優有, 石澤 有紀, 今西 正樹, 座間味 義人, 木平 孝高, 池田 康将, 土屋 浩一郎, 玉置 俊晃, 石澤 啓介
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-03-27
• [Presentation] Development of endothelial dysfunction-induced aortic dissection model and search for a preventive strategy (2016)
  • Author(s): 石澤 有紀, 今西 正樹, 木平 孝高, 宮本 理人, 座間味 義人, 池田 康将, 玉置 俊晃, 土屋 浩一郎, 石澤 啓介
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-03-09
• [Presentation] 高リン刺激は血管平滑筋細胞においてrho-kinase-cyclophilin A経路を活性化させる, (2016)
  • Author(s): 石澤 有紀, 石澤 啓介, 鍵本 優有, 斎藤 尚子, 高田 真衣, 木平 孝高, 今西 正樹, 池田 康将, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第45回日本心脈管作動物質学会
  • Place of Presentation: 阿波観光ホテル（徳島県・徳島市）
  • Year and Date: 2016-02-05
• [Presentation] 大動脈瘤形成における平滑筋由来HIF-1αの役割 (2016)
  • Author(s): 今西正樹、松永慎司、石澤啓介、玉置俊晃、冨田修平
  • Organizer: 第26回日本循環薬理学会
  • Place of Presentation: 信州大学（長野県松本市）
  • Int'l Joint Research
• [Presentation] 大動脈解離発症における内皮障害の関与 (2015)
  • Author(s): 斎藤 尚子, 石澤 有紀, 石澤 啓介, 戸谷 紘基, 今西 正樹, 鍵本 優有, 細岡 真由子, 木平 孝高, 池田 康将, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第25回日本循環薬理学会
  • Place of Presentation: 東大寺総合文化センター（奈良県・奈良市）
  • Year and Date: 2015-12-04
• [Presentation] 大動脈解離発症における内皮障害の関与の検討 (2015)
  • Author(s): 戸谷 紘基, 石澤 啓介, 石澤 有紀, 細岡 真由子, 鍵本 優有, 斎藤 尚子, 宮本 理人, 木平 孝高, 池田 康将, 玉置 俊晃, 土屋 浩一郎
  • Organizer: 第54回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会
  • Place of Presentation: 高知市文化プラザ、かるぽーと（高知県・高知市）
  • Year and Date: 2015-10-31
• [Presentation] 血管石灰化シグナルにおけるRhoキナーゼおよびサイクロフィリンAの関与 (2015)
  • Author(s): 石澤 有紀, 石澤 啓介, 大越 瑞穂, 土肥 紗希子, 木平 孝高, 池田 康将, 玉置 俊晃
  • Organizer: 第47回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2015-07-09