Investigation of cardiovascular regulation based on the association with autonomic nerve and brain-gut peptides

• Project/Area Number: 25293188
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: MIYAZATO Mikiya 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (50291183)
• Co-Investigator(Renkei-kenkyūsha): KISHIMOTO Ichiro 国立研究開発法人国立循環器病研究センター, 病院, 医長 (80312221) ; DATE Yukari 宮崎大学, 副学長 (70381100)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: ペプチド / グレリン / ニューロメジン / 自律神経 / 循環調節

Outline of Final Research Achievements

To clarify how the brain-gut peptide affects the cardiovascular regulatory system via the autonomic nerve, 1) we investigated the effect of ghrelin on myocardial infarction and cardiac hypertrophy models in ghrelin knockout mice, demonstrating that endogenous ghrelin suppresses sympathetic nerve activity and protects cardiac function after myocardial infarction and attenuates hypertrophy via a cholinergic anti-inflammatory pathway, 2) we developed selective agonists to neuromedin U receptors types 1 and 2 as tools for NMU/NMS-related research, 3) we selected orphan receptors expressed in the vagus nerve ganglion and searched for their endogenous ligands to find novel bioactive substances related to cardiovascular and autonomic nervous regulations.

Research Products

• [Journal Article] Importance of endogenous atrial and brain natriuretic peptides in murine embryonic vascular and organ development. (2016)
  • Author(s): Tokudome T, Kishimoto I, Shindo T, Kawakami H, Koyama T, Otani K, Nishimura H, Miyazato M, Kohno M, Nakao K, Kangawa K.
  • Journal Title: Endocrinology Volume: 157 Issue: 1 Pages: 358-367
  • DOI: 10.1210/en.2015-1344
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Involvement of endogenous neuromedin U and neuromedin S in thermoregulation. (2016)
  • Author(s): Nakahara K, Akagi A, Shimizu S, Tateno S, Qattali AW, Mori K, Miyazato M, Kangawa K, and Murakami N
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 470 Issue: 4 Pages: 930-935
  • DOI: 10.1016/j.bbrc.2016.01.155
  • Peer Reviewed / Open Access
• [Journal Article] Endogenous Ghrelin Attenuates Pressure Overload-Induced Cardiac Hypertrophy via a Cholinergic Anti-Inflammatory Pathway (2015)
  • Author(s): Mao Y, Tokudome T, Kishimoto I, Otani K, Nishimura H, Yamaguchi O, Otsu K, Miyazato M, Kangawa K
  • Journal Title: Hypertension Volume: 65 Issue: 6 Pages: 1238-1244
  • DOI: 10.1161/hypertensionaha.114.04864
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Discovery of potent hexapeptide agonists to human neuromedin U receptor 1 and identification of their serum metabolites. (2015)
  • Author(s): Takayama K, Mori K, Sohma Y, Taketa K, Taguchi A, Yakushiji F, Minamino N, Miyazato M, Kangawa K, and Hayashi Y
  • Journal Title: ACS Med. Chem. Lett. Volume: 6 Issue: 3 Pages: 302-307
  • DOI: 10.1021/ml500494j
  • Peer Reviewed
• [Journal Article] Discovery of selective hexapeptide agonists to human neuromedin U receptors types 1 and 2 (2014)
  • Author(s): Takayama K, Mori K, Taketa K, Taguchi A, Yakushiji F, Minamino N, Miyazato M, Kangawa K, Hayashi Y
  • Journal Title: J Med Chem Volume: 57 Pages: 6583-6593
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ghrelin and the cardiovascular system (2014)
  • Author(s): Tokudome T, Kishimoto I, Miyazato M, Kangawa K
  • Journal Title: Front Horm Res Volume: 43 Pages: 125-133
  • DOI: 10.1159/000360593
  • ISBN: 9783318026733, 9783318026740
  • Peer Reviewed
• [Journal Article] One dose of oral hexarelin protects chronic cardiac function after myocardial infarction (2014)
  • Author(s): Mao Y, Tokudome T, Kishimoto I, Otani K, Miyazato M, Kangawa K
  • Journal Title: Peptides Volume: 56 Pages: 156-162
  • DOI: 10.1016/j.peptides.2014.04.004
  • Peer Reviewed / Open Access
• [Journal Article] Hexarelin treatment in male ghrelin knockout mice after myocardial infarction (2013)
  • Author(s): Mao Y, Tokudome T, Kishimoto I, Otani K, Hosoda H, Nagai C, Minamino N, Miyazato M, Kangawa K
  • Journal Title: Endocrinology Volume: 154 Issue: 10 Pages: 3847-3845
  • DOI: 10.1210/en.2013-1291
  • Peer Reviewed
• [Journal Article] Metabolic features of rats resistant to a high-fat diet (2013)
  • Author(s): S. Akieda-Asai, S. Koda, M. Sugiyama, M. Furuya, M. Miyazato, and Y. Date
  • Journal Title: Obesity Research & Clinical Practice Volume: 7 Issue: 4 Pages: e243-e250
  • DOI: 10.1016/j.orcp.2013.01.004
  • Peer Reviewed
• [Journal Article] Excessive sympathoactivation and deteriorated heart function after myocardial infarction in male ghrelin knockout mice (2013)
  • Author(s): Mao Y, Tokudome T, Otani K, Kishimoto I, Miyazato M, Kangawa K
  • Journal Title: Endocrinology Volume: 154 Issue: 5 Pages: 1854-1863
  • DOI: 10.1210/en.2012-2132
  • Peer Reviewed
• [Presentation] 生理活性ペプチドの循環器疾患治療への応用の可能性～グレリンについて～ (2015)
  • Author(s): 宮里幹也、徳留健、岸本一郎、寒川賢治
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23