Clarification of ERK5-mediated endothelial mesenchymal transition suppression mechanism and its application to the prevention of arteriosclerosis

• Project/Area Number: 16K08549
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: The University of Tokushima
• Principal Investigator: IZAWA-ISHIZAWA Yuki 徳島大学, AWAサポートセンター, 准教授 (40610192)
• Co-Investigator(Kenkyū-buntansha): 池田 康将 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (60432754) ; 今西 正樹 徳島大学, 病院, 助教 (00734344)
• Research Collaborator: ABE Jun-ichi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 内皮間葉転換 / 動脈硬化 / ERK5 / 血管内皮細胞 / 動脈硬化性疾患 / ポリフェノール / 一酸化窒素合成酵素 / スタチン / 薬理学 / シグナル伝達 / 循環器・高血圧 / 糖尿病

Outline of Final Research Achievements

A study was conducted to clarify the involvement of ERK5 activation and endothelial mesenchymal transition (EndMT) in the arteriosclerosis-related diseases. Statins and quercetin, a kind of polyphenol, increased the expression of nitric oxide synthase (NOS) through ERK5 activation in cultured vascular endothelial cells. It was revealed that VE-cadherin expression, which is an endothelial cell marker involved in EndMT, is also increased in accordance with the increase or decrease of NOS expression. The vascular endothelial cell protective effect of these drugs was also confirmed from the improvement of the vascular injury caused by nitric oxide synthase inhibitor administration in mice. From the above, it is suggested that ERK5 activation may contribute to the prevention of the onset of the arteriosclerosis-related diseases.

Academic Significance and Societal Importance of the Research Achievements

粥状動脈硬化や大動脈瘤、大動脈解離、虚血性心疾患、脳卒中など、高血圧や加齢などを基礎疾患とする動脈硬化性疾患は、今なお日本人の主な死亡原因を占めているのが現状である。動脈硬化巣の形成は慢性的に進行するが、それに伴っておこる心血管イベントは予兆なく急激に発症し、致死的な転機をたどることも少なくない。そのため、イベント発症機序を明らかにし、予防戦略を確立することは非常に社会的意義がある。本研究課題では内皮間葉転換に着目し、内皮細胞におけるERK5活性化が動脈硬化性疾患のイベント発症予防に貢献し得る可能性を見出した。

Research Products

• [Journal Article] Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses (2019)
  • Author(s): Izawa-Ishizawa Yuki、Imanishi Masaki、Zamami Yoshito、Toya Hiroki、Nagao Tomoko、Morishita Marin、Tsuneyama Koichi、Horinouchi Yuya、Kihira Yoshitaka、Takechi Kenshi、Ikeda Yasumasa、Tsuchiya Koichiro、Yoshizumi Masanori、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Journal of Hypertension Volume: 37 Issue: 1 Pages: 73-83
  • DOI: 10.1097/hjh.0000000000001898
  • NAID: 120006627861
  • Peer Reviewed / Open Access
• [Journal Article] Xanthine oxidase inhibition by febuxostat in macrophages suppresses angiotensin II-induced aortic fibrosis (2018)
  • Author(s): Kondo Masateru、Imanishi Masaki、Fukushima Keijo、Ikuto Raiki、Murai Yoichi、Horinouchi Yuya、Izawa-Ishizawa Yuki、Goda Mitsuhiro、Zamami Yoshito、Takechi Kenshi、Chuma Masayuki、Ikeda Yasumasa、Fujino Hiromichi、Tsuchiya Koichiro、Ishizawa Keisuke
  • Journal Title: American Journal of Hypertension Volume: 32 Issue: 3 Pages: 249-256
  • DOI: 10.1093/ajh/hpy157
  • Peer Reviewed / Open Access
• [Journal Article] Nitrosonifedipine, a photodegradation product of nifedipine, suppresses pharmacologically induced aortic aneurysm formation (2018)
  • Author(s): Imanishi Masaki、Izawa-Ishizawa Yuki、Sakurada Takumi、Kohara Yusuke、Horinouchi Yuya、Sairyo Eriko、Zamami Yoshito、Takechi Kenshi、Chuma Masayuki、Fukushima Keijo、Ikeda Yasumasa、Fujino Hiromichi、Yoshizumi Masanori、Tsuchiya Koichiro、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Pharmacology Volume: 102 Issue: 5-6 Pages: 287-299
  • DOI: 10.1159/000492577
  • Peer Reviewed / Open Access
• [Journal Article] Irinotecan-induced neutropenia is reduced by oral alkalization drugs: analysis using retrospective chart reviews and the spontaneous reporting database (2018)
  • Author(s): Hamano Hirofumi、Mitsui Marin、Zamami Yoshito、Takechi Kenshi、Nimura Takahiro、Okada Naoto、Fukushima Keijo、Imanishi Masaki、Chuma Masayuki、Horinouchi Yuya、Izawa-Ishizawa Yuki、Kirino Yasushi、Nakamura Toshimi、Teraoka Kazuhiko、Ikeda Yasumasa、Fujino Hiromichi、Yanagawa Hiroaki、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Supportive Care in Cancer Volume: 27 Issue: 3 Pages: 849-856
  • DOI: 10.1007/s00520-018-4367-y
  • Peer Reviewed / Open Access
• [Journal Article] Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis (2018)
  • Author(s): Horinouchi Yuya、Ikeda Yasumasa、Fukushima Keijo、Imanishi Masaki、Hamano Hirofumi、Izawa-Ishizawa Yuki、Zamami Yoshito、Takechi Kenshi、Miyamoto Licht、Fujino Hiromichi、Ishizawa Keisuke、Tsuchiya Koichiro、Tamaki Toshiaki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 10858-10858
  • DOI: 10.1038/s41598-018-29008-2
  • NAID: 120006535061
  • Peer Reviewed / Open Access
• [Journal Article] The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin 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, Toshiaki Tamaki
  • Journal Title: Nephrology Dialysis Transplantation Volume: - Issue: 4 Pages: 586-597
  • DOI: 10.1093/ndt/gfx252
  • 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] Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia. (2017)
  • Author(s): Shiho Sato, Yoshito Zamami, Toru Imai, Satoshi Tanaka, Toshihiro Koyama, Takahiro Niimura, Masayuki Chuma, Tadashi Koga, Kenshi Takechi, Yasuko Kurata, Yutaka Kondo, Yuki Izawa-Ishizawa, Toshiaki Sendo, Hironori Nakura, Keisuke Ishizawa
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12683-12683
  • DOI: 10.1038/s41598-017-13073-0
  • Peer Reviewed / Open Access
• [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] Iron suppresses erythropoietin expression via oxidative stress-dependent hypoxia-inducible factor-2 alpha inactivation. (2017)
  • Author(s): Oshima K, Ikeda Y, Horinouchi Y, Watanabe H, Hamano H, Kihira Y, Kishi S, Izawa-Ishizawa Y, Miyamoto L, Hirayama T, Nagasawa H, Ishizawa K, Tsuchiya K, Tamaki T
  • Journal Title: Laboratory Investigation. Volume: 印刷中 Issue: 5 Pages: 555-566
  • DOI: 10.1038/labinvest.2017.11
  • NAID: 120006763916
  • Peer Reviewed
• [Journal Article] Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model. (2017)
  • Author(s): Yutaka Fukunaga, Yuki Izawa-Ishizawa, Yuya Horinouchi, Eriko Sairyo, Yasumasa Ikeda, Keisuke Ishizawa, Koichiro Tsuchiya, Yoshiro Abe, Ichiro Hashimoto, Toshiaki Tamaki.
  • Journal Title: Wound Repair and Regeneration Volume: 印刷中 Issue: 2 Pages: 217-223
  • DOI: 10.1111/wrr.12510
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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
• [Presentation] 薬剤誘発性大動脈瘤または大動脈解離モデルマウスに対するケルセチンの効果 (2019)
  • Author(s): 鈴木琴子、石澤有紀、近藤正輝、今西正樹、座間味義人、堀ノ内裕也、武智研志、合田光寛、中馬真幸、池田康将、石澤啓介
  • Organizer: 第92回日本薬理学会年会
• [Presentation] The effect of quercetin on aortic aneurysms in mice (2018)
  • Author(s): Yuki Izawa-Ishizawa, Masaki Imanishi, Kotoko Suzuki, Yuya Horinouchi Kenshi Takechi, Yoshito Zamami, Koichiro Tsuchiya, Toshiaki Tamaki Keisuke Ishizawa, Yasumasa Ikeda
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology；WCP2018
  • Int'l Joint Research
• [Presentation] Search for drugs that attenuate the antitumor effect of bevacizumab using adverse event database (2018)
  • Author(s): Yoshito Zamami, Yuki Izawa-Ishizawa, Kenshi Takechi, Masaki Imanishi, Keijo Fukushima, Yuya Horinouchi, Yasumasa Ikeda, Hiromichi Fujino, Toshiaki Tamaki, Keisuke Ishizawa
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology；WCP2018
  • Int'l Joint Research
• [Presentation] Nitrosonifedipine Ameliorates Neurological Symptoms and Prolongs the Survival in Malignant Stroke-Prone Spontaneously Hypertensive Rats (2018)
  • Author(s): Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Toshiaki Tamaki, Keisuke Ishizawa
  • Organizer: Society for Neuroscience Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] 線維芽細胞特異的ERK5欠損は腫瘍血管構造を変化させ腫瘍組織増大を促進させる (2018)
  • Author(s): 今西正樹、石澤有紀、山川裕介、常山幸一、福島圭穣、生藤来希、前川晃子、堀ノ内裕也、木宿昌俊、合田光寛、座間味義人、武智研志、中馬真幸、池田康将、藤野裕道、石澤啓介
  • Organizer: 日本循環薬理学会
• [Presentation] 新規大動脈解離モデルマウスの開発と予防薬の探索 (2018)
  • Author(s): 石澤有紀
  • Organizer: 第４回しこくオープンイノベーションワークショップin徳島
  • Invited
• [Presentation] 動脈硬化性疾患発症に対するケルセチンの効果 (2018)
  • Author(s): 石澤 有紀1, 鍵本 優有2, 今西 正樹3, 岩田 悠佑1,4, 鈴木 琴子2, 堀ノ内 裕也1, 武智 研志5, 座間味 義人2,3, 池田 康将1, 石澤 啓介2,3, 玉置 俊晃
  • Organizer: 第257回徳島医学会2018
  • Invited
• [Presentation] マウス大動脈瘤形成に対するケルセチンの効果 (2018)
  • Author(s): 石澤有紀, 鍵本優有, 今西正樹, 岩田悠佑, 堀ノ内裕也, 武智研志, 座間味義人, 池田康将, 石澤啓介, 玉置俊晃
  • Organizer: 第256回 徳島医学会学術集会（平成29年度冬期）
• [Presentation] ケルセチンの内皮保護作用を介したマウス大動脈解離発症に対する効果 (2017)
  • Author(s): 石澤有紀、細岡真由子、斎藤尚子、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、石澤啓介、玉置俊晃
  • 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
• [Presentation] ケルセチンによるマウス大動脈解離発症予防効果の検討 (2017)
  • Author(s): 石澤有紀、細岡真由子、斎藤尚子、鍵本優有、今西正樹、座間味義人、堀ノ内裕也、池田康将、土屋浩一郎、石澤啓介、玉置俊晃
  • 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
• [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
• [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] Nitrosonifedipine, a Novel Antioxidant, Ameliorates Neurological Symptoms and Prolongs the Survival in a Malignant Stroke-Prone Spontaneously Hypertensive Rats (2017)
  • Author(s): Yuki Izawa-Ishizawa, Keisuke Ishizawa, Masaki Tabuchi, Masaki Imanishi, Mai Takata, Eriko Sairyo, Yuya Yoshito Zamami, Horinouchi, Yasumasa Ikeda, Koichiro Tsuchiya, Toshiaki Tamaki
  • Organizer: European Meeting of Hypertension and Cardiovascular Protection
  • Int'l Joint Research
• [Presentation] 有害事象自発報告データベースを切り口としたベバシズマブの抗腫瘍効果を減弱させる薬剤の探索研究 (2017)
  • Author(s): 座間味義人, 石澤有紀, 桐野靖, 三井茉綸, 漆崎汐里, 武智研志, 今西正樹, 堀ノ内裕也, 池田康将, 藤野裕道, 土屋浩一郎, 玉置俊晃, 石澤啓介
  • Organizer: 医療薬学フォーラム 2017／第25回クリニカルファーマシーシンポジウム
• [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] 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] ニトロソニフェジピンは虚血性皮弁モデルにおいて皮弁壊死を抑制する (2016)
  • Author(s): 石澤有紀、福永豊、西良恵理子、今西正樹、堀ノ内裕也、池田康将、座間味義人、武智研志、石澤啓介、土屋浩一郎、橋本一郎、玉置俊晃
  • 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）
  • Year and Date: 2016-12-02
• [Presentation] Quercetin による血管内皮細胞保護効果の検討 (2016)
  • Author(s): 細岡 真由子, 石澤有紀、斎藤尚子、今西正樹、座間味義人、宮本理人、堀ノ内裕也、池田康将、石澤啓介、玉置俊晃、土屋浩一郎
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都大学百周年時計台記念館（京都府京都市）
  • Year and Date: 2016-11-19
• [Presentation] Disruption of hypoxia-inducible factor-1a deteriorates renal ischemia-reperfusion injury through dysregulation of Kv2.2-induced apoptosis in tubules. (2016)
  • Author(s): Kazuma Ota, Yoshitaka Kihira, Reina Kishibuchi, Yuki Izawa-Ishizawa, Yuya Horinouchi, Yasumasa Ikeda, Toshiaki Tamaki
  • Organizer: ASN KIDNEY WEEK 2016
  • Place of Presentation: シカゴ（アメリカ）
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [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] 虚血性皮弁壊死モデルにおける抗酸化薬ニトロソニフェジピンの壊死抑制効果 (2016)
  • Author(s): 福永豊、石澤有紀、堀ノ内裕也、池田康将、石澤啓介、土屋浩一郎、玉置俊晃, 橋本一郎
  • Organizer: 第25回日本形成外科学会基礎学術集会
  • Place of Presentation: ナレッジキャピタル（大阪府大阪市）
  • Year and Date: 2016-09-15
• [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
• [Presentation] ケルセチン代謝産物Q3GAの血管内皮膚細胞に対する短期及び長期効果の検討 (2016)
  • Author(s): 石澤有紀、細岡真由子、斎藤尚子、堀ノ内裕也、今西正樹、座間味義人、池田康将、石澤啓介、土屋浩一郎、玉置俊晃
  • Organizer: 第129回日本薬理学会近畿部会
  • Place of Presentation: 広島県医師会館（広島県広島市）
  • Year and Date: 2016-06-24
• [Presentation] The new insight of iron on tissue damage in metabolic disorders. (2016)
  • Author(s): Yasumasa Ikeda, Yuya Horinouchi, Yuki Izawa-Ishizawa, Toshiaki Tamaki.
  • 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 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, Oshima Keisuke, Horinouchi Yuya, 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