Development of innovative therapy of metabolic syndrome applying physiological effects of cardiac hormones

• Project/Area Number: 17K09897
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Tokudome Takeshi 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (00443474)
• Co-Investigator(Kenkyū-buntansha): 大谷 健太郎 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (50470191)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: メタボリックシンドローム / 血管内皮 / ANP / BNP / GC-A / ナトリウム利尿ペプチド / インスリン抵抗性 / 骨格筋血流 / 心臓ホルモン / 内科 / 内分泌学

Outline of Final Research Achievements

Metabolic syndrome is an accumulation of risk for lifestyle-related diseases based on the excessive accumulation of visceral fat. On the other hand, the heart produce and secrete atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which bind to a common receptor, Guanylyl Cyclase-A (GC-A), a common receptor , to exert its physiological effects. The present study confirmed that short-term administration of physiological concentrations of ANP to healthy mice does not affect their metabolism. On the other hand, vascular endothelial-specific GC-A deficient mice showed impaired metabolic function compared to control mice.

Academic Significance and Societal Importance of the Research Achievements

心臓ホルモンであるANP・BNPが代謝機能を改善するという報告は存在するが、脂肪組織や骨格筋に対するANP・BNPの作用に注目したものが多い。本研究ではANP・BNPの共通受容体GC-Aが血管内皮に豊富に発現していることを示し、かつ内皮特異的GC-A欠損マウスでは耐糖能障害・熱産生量低下が生じていることも明らかにした。一方生理的濃度のANPを健常マウスに短期間投与しても代謝には影響を及ぼさないことが確認された。ANP・BNPの分解酵素阻害作用を有する薬剤は慢性心不全治療薬として世界で臨床応用されており、長期間の服用により血管内皮機能向上を介した代謝機能改善効果をもたらすことが期待される。

Research Products

• [Journal Article] Deficiency of natriuretic peptide signaling promotes peripartum cardiomyopathy-like remodeling in the mouse heart. (2020)
  • Author(s): Otani K, Tokudome T, Kamiya CA, Mao Y, Nishimura H, Hasegawa T, Arai Y, Kaneko M, Shioi G, Ishida J, Fukamizu A, Osaki T, Nagai-Okatani C, Minamino N, Ensho T, Hino J, Murata S, Takegami M, Nishimura K, Kishimoto I, Miyazato M, Harada-Shiba M, Yoshimatsu J, Nakao K, Ikeda T, Kangawa K.
  • Journal Title: Circulation Volume: 141 Issue: 7 Pages: 571-588
  • DOI: 10.1161/circulationaha.119.039761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physiological significance of ghrelin in the cardiovascular system (2019)
  • Author(s): Tokudome T, Kangawa K
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 95 Issue: 8 Pages: 459-467
  • DOI: 10.2183/pjab.95.032
  • NAID: 130007728133
  • ISSN: 0386-2208, 1349-2896
  • Year and Date: 2019-10-11
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin and the heart (2019)
  • Author(s): Tokudome T, Otani K, Miyazato M, Kangawa K
  • Journal Title: Peptides Volume: 111 Pages: 42-46
  • DOI: 10.1016/j.peptides.2018.05.006
  • Peer Reviewed / Open Access
• [Journal Article] A New Secretory Peptide of Natriuretic Peptide Family,Osteocrin, Suppresses the Progression of Congestive Heart Failure After Myocardial Infarction. (2018)
  • Author(s): Miyazaki T, Otani K, Chiba A, Nishimura H, Tokudome T, Takano-Watanabe H, Matsuo A, Ishikawa H, Shimamoto K, Fukui H, Kanai Y, Yasoda A, Ogata S, Nishimura K, Minamino N, Mochizuki N.
  • Journal Title: Circ Res. Volume: 122(5) Issue: 5 Pages: 742-751
  • DOI: 10.1161/circresaha.117.312624
  • Peer Reviewed / Open Access
• [Journal Article] Adipocyte-specific expression of C-type natriuretic peptide suppresses lipid metabolism and adipocyte hypertrophy in adipose tissues in mice fed high-fat diet. (2018)
  • Author(s): Bae CR, Hino J, Hosoda H, Son C, Makino H, Tokudome T, Tomita T, Hosoda K, Miyazato M, Kangawa K.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2093-2093
  • DOI: 10.1038/s41598-018-20469-z
  • Peer Reviewed / Open Access
• [Journal Article] Guanylyl cyclase A in both renal proximal tubular and vascular endothelial cells protects the kidney against acute injury in rodent experimental endotoxemia models. (2018)
  • Author(s): Kidney against Acute Injury in Rodent Experimental Endotoxemia Models. Kitamura H, Nakano D, Sawanobori Y, Asaga T, Yokoi H, Yanagita M, Mukoyama M, Tokudome T, Kangawa K, Shirakami G, Nishiyama A.
  • Journal Title: Anesthesiology Volume: 印刷中 Issue: 2 Pages: 296-310
  • DOI: 10.1097/aln.0000000000002214
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells (2018)
  • Author(s): Ishikane S, Hosoda H, Nojiri T, Tokudome T, Mizutani T, Miura K, Akitake Y, Kimura T, Imamichi Y, Kawabe S, Toyohira Y, Yanagihara N, Takahashi-Yanaga F, Miyazato M, Miyamoto K, Kangawa K
  • Journal Title: Biochemical Pharmacology Volume: 154 Pages: 136-147
  • DOI: 10.1016/j.bcp.2018.04.012
  • Peer Reviewed
• [Journal Article] Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition. (2017)
  • Author(s): Y. Kato, K. Mori, M. Kasahara, K. Osaki, A. Ishii, K.P. Mori, N. Toda, S. Ohno, T. Kuwabara, T. Tokudome, I. Kishimoto, M.A. Saleem, T. Matsusaka, K. Nakao, M. Mukoyama, M. Yanagita, H. Yokoi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 46624-46624
  • DOI: 10.1038/srep46624
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Overexpression of C-type Natriuretic Peptide in Endothelial Cells Protects against Insulin Resistance and Inflammation during Diet-induced Obesity. (2017)
  • Author(s): Bae CR, Hino J, Hosoda H, Arai Y, Son C, Makino H, Tokudome T, Tomita T, Kimura T, Nojiri T, Hosoda K, Miyazato M, Kangawa K.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 9807-9807
  • DOI: 10.1038/s41598-017-10240-1
  • Peer Reviewed / Open Access
• [Presentation] ナトリウム利尿ペプチド研究の最前線 (2020)
  • Author(s): 徳留 健
  • Organizer: 第84回日本循環器学会学術集会
  • Invited
• [Presentation] 内因性心臓ナトリウム利尿ペプチドが摂食およびエネルギー代謝に及ぼす影響についての検討 (2019)
  • Author(s): 徳留 健
  • Organizer: 第42回日本高血圧学会総会
• [Presentation] Atrial natriuretic peptide exerts hypotensive effect via regulator f G-protein signaling 2-mediated endothelial hyperpolarization (2019)
  • Author(s): 徳留 健
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 周産期心筋症におけるナトリウム利尿ペプチド系の病態生理学的意義 (2018)
  • Author(s): 徳留 健
  • Organizer: 第7回臨床高血圧フォーラム
  • Invited
• [Presentation] 組織特異的AT1a受容体ノックアウトマウスを用いた血圧制御の解析 (2018)
  • Author(s): 徳留 健
  • Organizer: 第54回高血圧関連疾患モデル学会学術総会
  • Invited
• [Presentation] Atrial natriuretic peptideによる血圧調節のメカニズム解析 (2018)
  • Author(s): 徳留 健
  • Organizer: 第41回日本高血圧学会総会
• [Presentation] 心房性ナトリウム利尿ペプチドによる血圧調節のメカニズム解析 (2017)
  • Author(s): 徳留 健
  • Organizer: 第53回高血圧関連疾患モデル学会学術総会
• [Remarks] 国立循環器病研究センター研究所 生化学部
  • URL: http://www.ncvc.go.jp/res/divisions/biochemistry/
• [Remarks]
  • URL: http://www.ncvc.go.jp/res/divisions/biochemistry/
• [Patent(Industrial Property Rights)] 周産期心筋症治療剤 (2020)
  • Inventor(s): 大谷健太郎, 徳留 健, 神谷千津子
  • Industrial Property Rights Holder: 大谷健太郎, 徳留 健, 神谷千津子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020