A novel therapeutic approach for vascular failure by adrenomedullin-RAMP2 system

• Project/Area Number: 25893225
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto Prefectural University of Medicine (2014); International University of Health and Welfare (2013)
• Principal Investigator: KOYAMA Teruhide 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40711362)
• Research Collaborator: SHINDO Takayuki 信州大学, 医学系研究科, 教授
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アドレノメデュリン / RAMP2 / 血管内皮細胞 / 動脈硬化 / 血管恒常性 / 高血圧

Outline of Final Research Achievements

Adrenomedullin (AM) is a vasoactive peptide and its clinical applications are expected. AM’s receptor CLR interacts with one of the receptor activity-modifying proteins (RAMP1-3). We have suggested that vascular function of AM is mainly regulated by RAMP2. To clarify whether RAMP2 could be an alternative therapeutic target of AM, we generated and analyzed genetically engineered mice of RAMP2. We found that neointimal formation after vascular injury was markedly enhanced in vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-) compared with control mice. DI-E-RAMP2-/- also showed higher degree of oxidative stress and increased expression of inflammatory cytokines. Next, we generated vascular endothelial cell-specific RAMP2-overexpressing transgenic mice (E-RMAP2Tg). Contrary, intimal hyperplasia and inflammation was suppressed in E-RMAP2Tg compared with wild-type mice. These results suggest that RAMP2 could a novel therapeutic target for vascular failure.

Research Products

• [Journal Article] Pathophysiological roles of adrenomedullin and its receptor activity modifying system (2014)
  • Author(s): Shindo T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Koyama T.
  • Journal Title: Nihon Yakurigaku Zasshi Volume: 143 Pages: 232-5
  • NAID: 130004827694
  • Peer Reviewed
• [Journal Article] Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia (2014)
  • Author(s): Igarashi K, Tanaka M et al.
  • Journal Title: Peptides Volume: 62 Pages: 21-31
  • DOI: 10.1016/j.peptides.2014.08.013
  • Peer Reviewed / Open Access
• [Journal Article] Adrenomedullin-RAMP2 system is crucially involved in retinal angiogenesis (2013)
  • Author(s): Iesato Y, Tanaka M, et al.
  • Journal Title: Am J Pathol. Volume: 182 Issue: 6 Pages: 2380-90
  • DOI: 10.1016/j.ajpath.2013.02.015
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection (2013)
  • Author(s): Uetake R, Tanaka M, et al.
  • Journal Title: PLoS One. Volume: 9 Issue: 2 Pages: e87667-e87667
  • DOI: 10.1371/journal.pone.0087667
  • Peer Reviewed / Open Access
• [Journal Article] Endogenous CGEP protects against neointimal hyperplasia following wire-induced vascular injury (2012)
  • Author(s): Lei Yang, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Takahiro Yoshizawa, Tteruhide Kovama. Yasuhiro Iesato, Ryuichi Uetake, Akihiro Yamauchi, Megumu Tanaka, Yuichi Toriyama, Kyoko Igarashi, Takayuki Shindo
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 59 Pages: 55-56
  • DOI: 10.1016/j.yjmcc.2013.02.002
  • Peer Reviewed
• [Presentation] 急性および慢性脳虚血におけるAM-RAMP2系の神経保護作用 (2014)
  • Author(s): 五十嵐恭子, 桜井敬之, 神吉昭子, 新藤優佳, 河手久香, 山内啓弘, 鳥山佑一, 田中愛, Liu Tian, Xian Xian, 今井章, Zhai Liuyu, 大和慎治, 小山晃英, 新藤隆行
  • Organizer: 第26回日本脳循環代謝学会総会
  • Place of Presentation: 岡山
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis (2014)
  • Author(s): Koyama T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Iinuma N, Arai T, Yoshizawa T, Iesato Y, Yang L, Uetake R, Okimura A, Yamauchi A, Tanaka M, Igarashi K, Toriyama Y, Kawate H, Shindo T
  • Organizer: 第46回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 新宿
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] アドレノメデュリン-RAMP2系は、血管恒常性を維持し、「癌転移前土壌」の形成を抑制する (2014)
  • Author(s): 田中愛,小山晃英,桜井敬之,神吉昭子,植竹龍一,山内啓弘,五十嵐恭子, 鳥山佑一,劉甜,羨鮮,今井章,谷口俊一郎,新藤隆行
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 沖縄県名護市
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] アドレノメデュリン受容体システムの機能分化と、血管、リンパ管の制御機構 (2014)
  • Author(s): 山内啓弘, 桜井敬之, 神吉昭子, 河手久香, 新藤優佳, 小山晃英, 植竹龍一, 五十嵐恭子, 鳥山佑一, 田中愛, 劉甜, 羨鮮, 今井章, 新藤隆行
  • Organizer: 第38回日本リンパ学会総会
  • Place of Presentation: 北里大学薬学部コンベンションホール
  • Year and Date: 2014-06-20
• [Presentation] アドレノメデュリン－RAMP2系は、転移前土壌の形成を抑制する (2014)
  • Author(s): 田中愛、桜井敬之、神吉昭子、小山晃英、河手久香、新藤優佳、植竹龍一、山内啓弘、五十嵐恭子、鳥山佑一、羨鮮、劉甜、今井章、谷口俊一郎、新藤隆行
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 博多
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 腫瘍血管新生と転移におけるアドレノメデュリン－RAMP2系の意義
  • Author(s): 田中愛、小山晃英、桜井敬之、神吉昭子、楊磊、植竹龍一、山内啓弘、五十嵐恭子、鳥山佑一、新藤隆行
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 大阪
• [Presentation] 虚血性脳血管障害におけるアドレノメデュリン－RAMP2系の意義
  • Author(s): 五十嵐恭子、桜井敬之、神吉昭子、新藤優佳、小山晃英、楊磊、植竹龍一、山内啓弘、鳥山佑一、田中愛、河手久香、新藤隆行
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Significance of AM-RAMP2 system in tumor angiogenesis and metastasis
  • Author(s): Megumu Tanaka, Teruhide Koyama, Takayuki Sakurai, Akiko Kamiyoshi, Takahiro Yoshizawa, Lei Yang, Ryuichi Uetake, Akihiro Yamauchi, Kyoko Igarashi, Yuichi Toriyama, Takayuki Shindo
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] アドレノメデュリン受容体活性調節タンパクRAMP2およびRAMP3の脈管系における機能分化
  • Author(s): 山内啓弘、桜井敬之、神吉昭子、小山晃英、植竹龍一、五十嵐恭子、鳥山佑一、今井章、新藤優佳、新藤隆行
  • Organizer: 第17回日本心血管内分泌代謝学会
  • Place of Presentation: 大阪
• [Presentation] 腫瘍血管新生と転移におけるアドレノメデュリン－RAMP2システムの病態的意義
  • Author(s): 田中愛、小山晃英、桜井敬之、神吉昭子、楊磊、植竹龍一、山内啓弘、五十嵐恭子、鳥山佑一、新藤隆行
  • Organizer: 第17回日本心血管内分泌代謝学会
  • Place of Presentation: 大阪
• [Presentation] 血管内皮細胞のアドレノメデュリン-RAMP2系は、「転移前土壌」の形成を制御する
  • Author(s): 田中愛、桜井敬之、神吉昭子、小山晃英、河手久香、新藤優佳、植竹龍一、山内啓弘、五十嵐恭子、鳥山佑一、劉甜、羨鮮、今井章、新藤隆行
  • Organizer: 第43回日本心脈管作動物質学会
  • Place of Presentation: 神戸
• [Presentation] 血管・リンパ管制御における、アドレノメデュリン受容体AM1、AM2の機能分化
  • Author(s): 山内啓弘、桜井敬之、神吉昭子、河手久香、新藤優佳、小山晃英、植竹龍一、五十嵐恭子、鳥山佑一、田中愛、劉甜、羨鮮、今井章、新藤隆行
  • Organizer: 第43回日本心脈管作動物質学会
  • Place of Presentation: 神戸
• [Presentation] アドレノメデュリン-RAMP2系の急性および慢性脳虚血における病態生理学的意義
  • Author(s): 五十嵐恭子、桜井敬之、神吉昭子、河手久香、新藤優佳、小山晃英、植竹龍一、山内啓弘、鳥山佑一、田中愛、劉甜、羨鮮、今井章、新藤隆行
  • Organizer: 第43回日本心脈管作動物質学会
  • Place of Presentation: 神戸
• [Presentation] Adrenomedullin-RAMP2 system as a novel therapeutic target of tumor angiogenesis and metastasis
  • Author(s): Megumu Tanaka ,Teruhide Koyama ,Takayuki Sakurai ,Akiko Kamiyoshi ,Yuka Shindo ,Ryuichi Uetake ,Akihiro Yamauchi ,Kyoko Igarashi ,Yuichi Toriyama ,Xian Xian ,Tian Liu ,Akira Imai ,Shunichiro Taniguchi ,Takayuki Shindoh
  • Organizer: 第78回日本循環器学会
  • Place of Presentation: 東京
• [Presentation] Pathophysiological Roles of RAMP2 and RAMP3 in the Vascular System
  • Author(s): Akihiro Yamauchi ,Takayuki Sakurai ,Akiko Kamiyoshi ,Yuka Shindo ,Teruhide Koyama ,Ryuichi Uetake ,Kyoko Igarashi ,Yuichi Toriyama ,Megumu Tanaka ,Akira Imai ,Takayuki Shindoh
  • Organizer: 第78回日本循環器学会
  • Place of Presentation: 東京