Updated on 2026/03/10

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写真a

 
Takeshi Tokudome
 
Organization
Graduate School of Medicine Department of Medicine Pharmacology Professor
School of Medicine Medical Course
Title
Professor
Profile

循環器・腎臓・脳卒中内科で臨床研修後、国立循環器病研究センターに異動し、研究・臨床を約20年間行いました。

国循での研究を通じて「内分泌-神経-免疫連関」に興味を持ち、神経科学や免疫学を自身の研究に取り入れたいと強く願った結果、幸運にも令和5年(2023)年4月より、横浜市立大学医学部薬理学教室の主任教授を拝命しました。

疾患の長期予後を改善するとは、究極的には何がどうなることか？そのための治療標的はどこか？

内分泌系・神経系・免疫系といった生体恒常性維持システムの相互連関を研究しつつ、明らかにしたいと考えています。

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Research Interests

  • 遺伝子改変マウス

  • 急性炎症

  • 血圧調節

  • 自律神経系

  • 心不全

  • トランスレーショナルリサーチ

  • 慢性炎症

  • 血管生物学

  • ペプチドホルモン

  • 内分泌-神経-免疫連関

Research Areas

  • Life Science / Clinical pharmacy

  • Life Science / Physiology

  • Life Science / Pharmacology

Education

  • 香川医科大学大学院

    - 2000.3

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  • 香川医科大学医学部

    - 1996.3

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  • 鹿児島県立鶴丸高校

    - 1989.3

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Research History

  • 横浜市立大学医学部 薬理学教室   主任教授

    2023.4

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  • 国立循環器病研究センター研究所 心不全病態制御部 室長

    2022.4 - 2023.3

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  • 国立循環器病研究センター研究所 生化学部 室長

    2010.4 - 2022.3

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  • 国立循環器病センター研究所 病因部 高血圧研究室長

    2006.6 - 2010.3

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  • 国立循環器病センター 内科 シニアレジデント

    2005.4 - 2006.5

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  • PMDA派遣研究員

    2004.4 - 2005.3

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  • 国立循環器病センター研究所 生化学部 ポスドク

    2001.4 - 2004.3

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Professional Memberships

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Committee Memberships

  • 日本薬理学会   学術評議員  

       

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  • 日本心脈管作動物質学会   評議員  

       

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  • 日本心血管内分泌代謝学会   監事  

       

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  • 日本心不全学会   代議員  

       

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  • 日本高血圧学会   評議員  

       

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  • 日本生理学会   評議員  

       

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  • 日本内分泌学会   評議員  

       

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Papers

  • Endothelial Natriuretic Peptide Receptor 1 Play Crucial Role for Acute and Chronic Blood Pressure Regulation by Atrial Natriuretic Peptide. International journal

    Takeshi Tokudome, Kentaro Otani, Yuanjie Mao, Lars Jørn Jensen, Yuji Arai, Takahiro Miyazaki, Takashi Sonobe, James T Pearson, Tsukasa Osaki, Naoto Minamino, Junji Ishida, Akiyoshi Fukamizu, Hayato Kawakami, Daisuke Onozuka, Kunihiro Nishimura, Mikiya Miyazato, Hirohito Nishimura

    Hypertension (Dallas, Tex. : 1979)   79 ( 7 )   101161HYPERTENSIONAHA12118114 - 1422   2022.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP. METHODS AND RESULTS: Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell-specific Npr1-knockout mice but not in endothelial cell-specific Npr1-knockout mice. Moreover, ANP significantly lowered systolic blood pressure in Nos3-knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca2+ concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased Rgs2 mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in Rgs2-knockout mice. Endothelial cell-specific Npr1-overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography. CONCLUSIONS: Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.

    DOI： 10.1161/HYPERTENSIONAHA.121.18114

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  • Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart. Reviewed International journal

    Kentaro Otani, Takeshi Tokudome, Chizuko A Kamiya, Yuanjie Mao, Hirohito Nishimura, Takeshi Hasegawa, Yuji Arai, Mari Kaneko, Go Shioi, Junji Ishida, Akiyoshi Fukamizu, Tsukasa Osaki, Chiaki Nagai-Okatani, Naoto Minamino, Takuya Ensho, Jun Hino, Shunsuke Murata, Misa Takegami, Kunihiro Nishimura, Ichiro Kishimoto, Mikiya Miyazato, Mariko Harada-Shiba, Jun Yoshimatsu, Kazuwa Nakao, Tomoaki Ikeda, Kenji Kangawa

    Circulation   141 ( 7 )   571 - 588   2020.2

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    BACKGROUND: The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood. METHODS: To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide-NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function. RESULTS: In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy-lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin-nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti-interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice. CONCLUSIONS: These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide-NPR1 system plays an important role in protecting the maternal heart from interleukin-6-induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.

    DOI： 10.1161/CIRCULATIONAHA.119.039761

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  • A New Secretory Peptide of Natriuretic Peptide Family, Osteocrin, Suppresses the Progression of Congestive Heart Failure After Myocardial Infarction. Reviewed International journal

    Takahiro Miyazaki, Kentaro Otani, Ayano Chiba, Hirohito Nishimura, Takeshi Tokudome, Haruko Takano-Watanabe, Ayaka Matsuo, Hiroyuki Ishikawa, Keiko Shimamoto, Hajime Fukui, Yugo Kanai, Akihiro Yasoda, Soshiro Ogata, Kunihiro Nishimura, Naoto Minamino, Naoki Mochizuki

    Circulation research   122 ( 5 )   742 - 751   2018.3

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

    DOI： 10.1161/CIRCRESAHA.117.312624

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  • Finerenone ameliorates diabetic kidney disease exacerbated by deletion of natriuretic peptide/guanylyl cyclase-A signaling and dietary high-protein load

    Yui Inoue, Akira Ishii, Takuya Ishimura, Hiroyuki Yamada, Sayaka Sugioka, Takaya Handa, Akie Ikushima, Haruomi Nishio, Yukiko Kato, Shoko Ohno, Yasuaki Nakagawa, Koichiro Kuwahara, Taiji Matsusaka, Takeshi Tokudome, Motoko Yanagita, Hideki Yokoi

    Scientific Reports   15 ( 1 )   2025.11

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1038/s41598-025-25362-0

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    Other Link： https://www.nature.com/articles/s41598-025-25362-0

  • Matrix metalloproteinase (MMP)-10 aggravates podocyte injury in glomerulonephritis

    Takuya Ishimura, Keisuke Osaki, Sayaka Sugioka, Akira Ishii, Hiroyuki Yamada, Naohiro Toda, Shoko Ohno, Yukiko Kato, Taiji Matsusaka, Takeshi Tokudome, Motoko Yanagita, Hideki Yokoi

    Nephrology Dialysis Transplantation   2025.5

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    Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

    ABSTRACT

    Background

    Podocytes are integral to maintaining glomerular filtration barrier. Our previous research underscored the crucial role of podocyte guanylyl cyclase-A (GC-A) in the pathogenesis of severe albuminuria in both systemic and podocyte-specific GC-A knockout mice subjected to heminephrectomy, high salt, and aldosterone (ALDO) treatment. This study investigates the role of matrix metalloproteinase-10 (MMP-10) on glomerular injury, which was found to be highly expressed in glomeruli of ALDO-treated GC-A knockout mice.

    Methods

    To investigate the role of MMP-10 in glomerulonephritis, we used MMP-10 knockout mice subjected to anti-glomerular basement membrane (GBM) nephritis. Additionally, we created systemic GC-A and MMP-10 double knockout mice, as well as podocyte-specific GC-A and systemic MMP-10 double knockout mice, to analyze glomerular injury. In vitro, changes in inflammatory mRNA are examined in MMP-10-overexpressing or -knockdown mouse podocytes following stimulation of tumor necrosis factor (TNF)-α.

    Results

    We demonstrate that MMP-10 is highly expressed in the kidneys of patients with glomerulonephritis. MMP-10 knockout mice showed less albuminuria and lower expression of pro-inflammatory and pro-fibrotic mRNAs compared to control mice in anti-GBM nephritis. Additionally, systemic or podocyte-specific GC-A and systemic MMP-10 knockout mice exhibited improved albuminuria, preserved nephrin expression, and reduced GBM thickening compared to systemic or podocyte-specific GC-A knockout mice with ALDO treatment. MMP-10 was co-localized with podocytes and endothelial cells. In vitro studies using mouse podocytes revealed that MMP-10 overexpression upregulated inflammatory mRNA changes induced by TNF-α, whereas MMP-10 knockdown mitigated inflammation. Co-culture of mouse podocytes with human endothelial cells showed reduced inflammation following MMP-10 reduction in endothelial cells. Moreover, activated MMP-10 cleaved nephrin in vitro, contributing to podocyte injury.

    Conclusion

    These findings suggest that GC-A ablation leads to upregulation of MMP-10, resulting in nephrin loss, and that systemic deletion of MMP-10 ameliorates GC-A-induced podocyte injury.

    DOI： 10.1093/ndt/gfaf076

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  • Dual deletion of guanylyl cyclase-A and p38 mitogen-activated protein kinase in podocytes with aldosterone administration causes glomerular intra-capillary thrombi. International journal

    Sayaka Sugioka, Hiroyuki Yamada, Akira Ishii, Yukiko Kato, Ryo Yamada, Keita P Mori, Shoko Ohno, Takaya Handa, Akie Ikushima, Takuya Ishimura, Keisuke Osaki, Takeshi Tokudome, Taiji Matsusaka, Angel R Nebreda, Motoko Yanagita, Hideki Yokoi

    Kidney international   2023.6

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    Natriuretic peptides exert not only blood-lowering but also kidney-protective effects through guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. Signaling through GC-A has been shown to protect podocytes from aldosterone-induced glomerular injury, and a p38 mitogen-activated protein kinase (MAPK) inhibitor reduced glomerular injury in aldosterone-infused podocyte-specific GC-A knockout mice. To explore the role of p38 MAPK in podocytes, we constructed podocyte-specific p38 MAPK and GC-A double knockout mice (pod-double knockout mice). Unexpectedly, aldosterone-infused and high salt-fed (B-ALDO)-treated pod-double knockout mice resulted in elevated serum creatinine, massive albuminuria, macrophage infiltration, foot process effacement, nephrin and podocin reduction, and additionally, intra-capillary fibrin thrombi, indicating endothelial injury. Microarray analysis showed increased plasminogen activator inhibitor-1 (PAI-1) in glomeruli of B-ALDO-treated pod-double knockout mice. In B-ALDO-treated pod-double knockout mice, PAI-1 increased in podocytes, and treatment with PAI-1 neutralizing antibody ameliorated intra-capillary thrombus formation. In vitro, deletion of p38 MAPK by the CRISPR/Cas9 system and knockdown of GC-A in human cultured podocytes upregulated PAI-1 and transforming growth factor-β1 (TGF-β1). When p38 MAPK knockout podocytes, transfected with a small interfering RNA to suppress GC-A, were co-cultured with glomerular endothelial cells in a transwell system, the expression of TGF-β1 was increased in glomerular endothelial cells. PAI-1 inhibition ameliorated both podocyte and endothelial injury in the transwell system signifying elevated PAI-1 in podocytes is a factor disrupting normal podocyte-endothelial crosstalk. Thus, our results indicate that genetic dual deletion of p38 MAPK and GC-A in podocytes accelerates both podocyte and endothelial injuries, suggesting these two molecules play indispensable roles in podocyte function.

    DOI： 10.1016/j.kint.2023.06.007

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  • Molecular Mechanism of Blood Pressure Regulation through the Atrial Natriuretic Peptide. International journal

    Takeshi Tokudome, Kentaro Otani

    Biology   11 ( 9 )   2022.9

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    Natriuretic peptides, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), have cardioprotective effects and regulate blood pressure in mammals. ANP and BNP are hormones secreted from the heart into the bloodstream in response to increased preload and afterload. Both hormones act through natriuretic peptide receptor 1 (NPR1). In contrast, CNP acts through natriuretic peptide receptor 2 (NPR2) and was found to be produced by the vascular endothelium, chondrocytes, and cardiac fibroblasts. Based on its relatively low plasma concentration compared with ANP and BNP, CNP is thought to function as both an autocrine and a paracrine factor in the vasculature, bone, and heart. The cytoplasmic domains of both NPR1 and NPR2 display a guanylate cyclase activity that catalyzes the formation of cyclic GMP. NPR3 lacks this guanylate cyclase activity and is reportedly coupled to Gi-dependent signaling. Recently, we reported that the continuous infusion of the peptide osteocrin, an endogenous ligand of NPR3 secreted by bone and muscle cells, lowered blood pressure in wild-type mice, suggesting that endogenous natriuretic peptides play major roles in the regulation of blood pressure. Neprilysin is a neutral endopeptidase that degrades several vasoactive peptides, including natriuretic peptides. The increased worldwide clinical use of the angiotensin receptor-neprilysin inhibitor for the treatment of chronic heart failure has brought renewed attention to the physiological effects of natriuretic peptides. In this review, we provide an overview of the discovery of ANP and its translational research. We also highlight our recent findings on the blood pressure regulatory effects of ANP, focusing on its molecular mechanisms.

    DOI： 10.3390/biology11091351

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  • Ghrelin and the heart. Reviewed International journal

    Takeshi Tokudome, Kentaro Otani, Mikiya Miyazato, Kenji Kangawa

    Peptides   111   42 - 46   2019.1

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

    DOI： 10.1016/j.peptides.2018.05.006

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  • Physiological significance of ghrelin in the cardiovascular system. Reviewed

    Takeshi Tokudome, Kenji Kangawa

    Proceedings of the Japan Academy. Series B, Physical and biological sciences   95 ( 8 )   459 - 467   2019

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    Ghrelin, a growth hormone-releasing peptide first discovered in rat stomach in 1999, is a ligand for the growth hormone secretagogue receptor. It participates in the regulation of diverse processes, including energy balance and body weight maintenance, and appears to be beneficial for the treatment of cardiovascular diseases. In animal models of chronic heart failure, ghrelin improves cardiac function and remodeling; these findings have been recapitulated in human patients. In other animal models, ghrelin effectively diminishes pulmonary hypertension. Moreover, ghrelin administration early after myocardial infarction decreased the frequency of fatal arrhythmia and improved survival rate. In ghrelin-deficient mice, endogenous ghrelin protects against fatal arrhythmia and promotes remodeling after myocardial infarction. Although the mechanisms underlying the effects of ghrelin on the cardiovascular system have not been fully elucidated, its beneficial effects appear to be mediated through regulation of the autonomic nervous system. Ghrelin is a promising therapeutic agent for cardiac diseases.

    DOI： 10.2183/pjab.95.032

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  • Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells. Reviewed International journal

    Shin Ishikane, Hiroshi Hosoda, Takashi Nojiri, Takeshi Tokudome, Tetsuya Mizutani, Koichi Miura, Yoshiharu Akitake, Toru Kimura, Yoshitaka Imamichi, Shinya Kawabe, Yumiko Toyohira, Nobuyuki Yanagihara, Fumi Takahashi-Yanaga, Mikiya Miyazato, Kaoru Miyamoto, Kenji Kangawa

    Biochemical pharmacology   154   136 - 147   2018.8

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    DOI： 10.1016/j.bcp.2018.04.012

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  • Guanylyl Cyclase A in Both Renal Proximal Tubular and Vascular Endothelial Cells Protects the Kidney against Acute Injury in Rodent Experimental Endotoxemia Models. Reviewed International journal

    Hiroaki Kitamura, Daisuke Nakano, Yoshiharu Sawanobori, Takehiko Asaga, Hideki Yokoi, Motoko Yanagita, Masashi Mukoyama, Takeshi Tokudome, Kenji Kangawa, Gotaro Shirakami, Akira Nishiyama

    Anesthesiology   129 ( 2 )   296 - 310   2018.8

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    WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Natriuretic peptides are used, based on empirical observations, in intensive care units as antioliguric treatments. We hypothesized that natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A, a receptor for natriuretic peptides, in proximal tubules and endothelial cells. METHODS: Normal Sprague-Dawley rats and mice lacking guanylyl cyclase A in either endothelial cells or proximal tubular cells were challenged with lipopolysaccharide and assessed for oliguria and intratubular flow rate by intravital imaging with multiphoton microscopy. RESULTS: Recombinant atrial natriuretic peptide efficiently improved urine volume without changing blood pressure after lipopolysaccharide challenge in rats (urine volume at 4 h, lipopolysaccharide: 0.6 ± 0.3 ml · kg · h; lipopolysaccharide + fluid resuscitation: 4.6 ± 2.0 ml · kg · h; lipopolysaccharide + fluid resuscitation + atrial natriuretic peptide: 9.0 ± 4.8 ml · kg · h; mean ± SD; n = 5 per group). Lipopolysaccharide decreased glomerular filtration rate and slowed intraproximal tubular flow rate, as measured by in vivo imaging. Fluid resuscitation restored glomerular filtration rate but not tubular flow rate. Adding atrial natriuretic peptide to fluid resuscitation improved both glomerular filtration rate and tubular flow rate. Mice lacking guanylyl cyclase A in either proximal tubules or endothelium demonstrated less improvement of tubular flow rate when treated with atrial natriuretic peptide, compared with control mice. Deletion of endothelial, but not proximal tubular, guanylyl cyclase A augmented the reduction of glomerular filtration rate by lipopolysaccharide. CONCLUSIONS: Both endogenous and exogenous natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A in proximal tubules and endothelial cells.

    DOI： 10.1097/ALN.0000000000002214

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  • Adipocyte-specific expression of C-type natriuretic peptide suppresses lipid metabolism and adipocyte hypertrophy in adipose tissues in mice fed high-fat diet. Reviewed International journal

    Cho-Rong Bae, Jun Hino, Hiroshi Hosoda, Cheol Son, Hisashi Makino, Takeshi Tokudome, Tsutomu Tomita, Kiminori Hosoda, Mikiya Miyazato, Kenji Kangawa

    Scientific reports   8 ( 1 )   2093 - 2093   2018.2

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    C-type natriuretic peptide (CNP) is expressed in diverse tissues, including adipose and endothelium, and exerts its effects by binding to and activating its receptor, guanylyl cyclase B. Natriuretic peptides regulate intracellular cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP). We recently revealed that overexpression of CNP in endothelial cells protects against high-fat diet (HFD)-induced obesity in mice. Given that endothelial CNP affects adipose tissue during obesity, CNP in adipocytes might directly regulate adipocyte function during obesity. Therefore, to elucidate the effect of CNP in adipocytes, we assessed 3T3-L1 adipocytes and transgenic (Tg) mice that overexpressed CNP specifically in adipocytes (A-CNP). We found that CNP activates the cGMP-VASP pathway in 3T3-L1 adipocytes. Compared with Wt mice, A-CNP Tg mice showed decreases in fat weight and adipocyte hypertrophy and increases in fatty acid β-oxidation, lipolysis-related gene expression, and energy expenditure during HFD-induced obesity. These effects led to decreased levels of the macrophage marker F4/80 in the mesenteric fat pad and reduced inflammation. Furthermore, A-CNP Tg mice showed improved glucose tolerance and insulin sensitivity, which were associated with enhanced insulin-stimulated Akt phosphorylation. Our results suggest that CNP overexpression in adipocytes protects against adipocyte hypertrophy, excess lipid metabolism, inflammation, and decreased insulin sensitivity during HFD-induced obesity.

    DOI： 10.1038/s41598-018-20469-z

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  • Overexpression of C-type Natriuretic Peptide in Endothelial Cells Protects against Insulin Resistance and Inflammation during Diet-induced Obesity. Reviewed International journal

    Cho-Rong Bae, Jun Hino, Hiroshi Hosoda, Yuji Arai, Cheol Son, Hisashi Makino, Takeshi Tokudome, Tsutomu Tomita, Toru Kimura, Takashi Nojiri, Kiminori Hosoda, Mikiya Miyazato, Kenji Kangawa

    Scientific reports   7 ( 1 )   9807 - 9807   2017.8

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    DOI： 10.1038/s41598-017-10240-1

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  • Preventive effect of renin-angiotensin system inhibitors on new-onset atrial fibrillation in hypertensive patients: a propensity score matching analysis Invited

    T. Horio, M. Akiyama, Y. Iwashima, F. Yoshihara, S. Nakamura, T. Tokudome, M. Okutsu, H. Tanaka, I. Komatsubara, N. Okimoto, S. Kamakura, Y. Kawano

    JOURNAL OF HUMAN HYPERTENSION   31 ( 7 )   450 - 456   2017.7

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    DOI： 10.1038/jhh.2016.95

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  • Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition. Reviewed International journal

    Yukiko Kato, Kiyoshi Mori, Masato Kasahara, Keisuke Osaki, Akira Ishii, Keita P Mori, Naohiro Toda, Shoko Ohno, Takashige Kuwabara, Takeshi Tokudome, Ichiro Kishimoto, Moin A Saleem, Taiji Matsusaka, Kazuwa Nakao, Masashi Mukoyama, Motoko Yanagita, Hideki Yokoi

    Scientific reports   7   46624 - 46624   2017.4

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    DOI： 10.1038/srep46624

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  • Endothelium-Derived C-Type Natriuretic Peptide Contributes to Blood Pressure Regulation by Maintaining Endothelial Integrity. Reviewed International journal

    Kazuhiro Nakao, Koichiro Kuwahara, Toshio Nishikimi, Yasuaki Nakagawa, Hideyuki Kinoshita, Takeya Minami, Yoshihiro Kuwabara, Chinatsu Yamada, Yuko Yamada, Takeshi Tokudome, Chiaki Nagai-Okatani, Naoto Minamino, Yoko M Nakao, Shinji Yasuno, Kenji Ueshima, Masakatsu Sone, Takeshi Kimura, Kenji Kangawa, Kazuwa Nakao

    Hypertension (Dallas, Tex. : 1979)   69 ( 2 )   286 - 296   2017.2

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    DOI： 10.1161/HYPERTENSIONAHA.116.08219

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  • Atrial natriuretic peptide protects against bleomycin-induced pulmonary fibrosis via vascular endothelial cells in mice ANP for pulmonary fibrosis Reviewed

    Atsuko Okamoto, Takashi Nojiri, Kazuhisa Konishi, Takeshi Tokudome, Koichi Miura, Hiroshi Hosoda, Jun Hino, Mikiya Miyazato, Yohkoh Kyomoto, Kazuhisa Asai, Kazuto Hirata, Kenji Kangawa

    RESPIRATORY RESEARCH   18   2017.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1186/s12931-016-0492-7

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  • Effects of Adrenomedullin on Doxorubicin-Induced Cardiac Damage in Mice. Reviewed

    Takahiro Yoshizawa, Sho Takizawa, Shin Shimada, Takeshi Tokudome, Takayuki Shindo, Kiyoshi Matsumoto

    Biological & pharmaceutical bulletin   39 ( 5 )   737 - 46   2016.5

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    DOI： 10.1248/bpb.b15-00832

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  • Ghrelin and Blood Pressure Regulation. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Ichiro Kishimoto

    Current hypertension reports   18 ( 2 )   15 - 15   2016.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1007/s11906-015-0622-5

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  • Importance of Endogenous Atrial and Brain Natriuretic Peptides in Murine Embryonic Vascular and Organ Development. Reviewed International journal

    Takeshi Tokudome, Ichiro Kishimoto, Takayuki Shindo, Hayato Kawakami, Teruhide Koyama, Kentaro Otani, Hirohito Nishimura, Mikiya Miyazato, Masakazu Kohno, Kazuwa Nakao, Kenji Kangawa

    Endocrinology   157 ( 1 )   358 - 67   2016.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1210/en.2015-1344

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  • Endogenous ghrelin attenuates pressure overload-induced cardiac hypertrophy via a cholinergic anti-inflammatory pathway. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Ichiro Kishimoto, Kentaro Otani, Hirohito Nishimura, Osamu Yamaguchi, Kinya Otsu, Mikiya Miyazato, Kenji Kangawa

    Hypertension (Dallas, Tex. : 1979)   65 ( 6 )   1238 - 44   2015.6

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    DOI： 10.1161/HYPERTENSIONAHA.114.04864

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  • Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides. Reviewed

    Fumiki Yoshihara, Takeshi Tokudome, Ichiro Kishimoto, Kentaro Otani, Atsunori Kuwabara, Takeshi Horio, Yuhei Kawano, Kenji Kangawa

    Clinical and experimental nephrology   19 ( 2 )   197 - 207   2015.4

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    DOI： 10.1007/s10157-014-0982-1

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  • ポドサイトにおけるNa利尿ペプチドGC-A受容体のp38MAPK抑制を介した腎保護作用

    加藤 有希子, 横井 秀基, 森 潔, 笠原 正登, 小川 喜久, 徳留 健, 岸本 一郎, 菅原 照, 松阪 泰二, 中尾 一和, 柳田 素子, 向山 政志

    日本臨床分子医学会学術総会プログラム・抄録集   52回   54 - 54   2015.4

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  • The cardiovascular action of hexarelin. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Ichiro Kishimoto

    Journal of geriatric cardiology : JGC   11 ( 3 )   253 - 8   2014.9

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    DOI： 10.11909/j.issn.1671-5411.2014.03.007

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  • Ghrelin as a treatment for cardiovascular diseases. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Ichiro Kishimoto

    Hypertension (Dallas, Tex. : 1979)   64 ( 3 )   450 - 4   2014.9

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    DOI： 10.1161/HYPERTENSIONAHA.114.03726

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  • One dose of oral hexarelin protects chronic cardiac function after myocardial infarction. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Ichiro Kishimoto, Kentaro Otani, Mikiya Miyazato, Kenji Kangawa

    Peptides   56   156 - 62   2014.6

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    DOI： 10.1016/j.peptides.2014.04.004

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  • Lack of salt-inducible kinase 2 (SIK2) prevents the development of cardiac hypertrophy in response to chronic high-salt intake. Reviewed International journal

    Sergej Popov, Hiroshi Takemori, Takeshi Tokudome, Yuanjie Mao, Kentaro Otani, Naoki Mochizuki, Nuno Pires, Maria João Pinho, Anders Franco-Cereceda, Lucia Torielli, Mara Ferrandi, Anders Hamsten, Patricio Soares-da-Silva, Per Eriksson, Alejandro M Bertorello, Laura Brion

    PloS one   9 ( 4 )   e95771   2014.4

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    DOI： 10.1371/journal.pone.0095771

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  • Ghrelin and the cardiovascular system. Reviewed International journal

    Takeshi Tokudome, Ichiro Kishimoto, Mikiya Miyazato, Kenj Kangawa

    Frontiers of hormone research   43   125 - 33   2014

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    DOI： 10.1159/000360593

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  • Hexarelin treatment in male ghrelin knockout mice after myocardial infarction. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Ichiro Kishimoto, Kentaro Otani, Hiroshi Hosoda, Chiaki Nagai, Naoto Minamino, Mikiya Miyazato, Kenji Kangawa

    Endocrinology   154 ( 10 )   3847 - 54   2013.10

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    DOI： 10.1210/en.2013-1291

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  • Excessive sympathoactivation and deteriorated heart function after myocardial infarction in male ghrelin knockout mice. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Kentaro Otani, Ichiro Kishimoto, Mikiya Miyazato, Kenji Kangawa

    Endocrinology   154 ( 5 )   1854 - 63   2013.5

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    DOI： 10.1210/en.2012-2132

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  • Ghrelin Reviewed

    Ichiro Kishimoto, Takeshi Tokudome, Hiroshi Hosoda, Mikiya Miyazato, Kenji Kangawa

    Handbook of Biologically Active Peptides   1408 - 1414   2013

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    DOI： 10.1016/B978-0-12-385095-9.00191-3

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  • Ghrelin prevents incidence of malignant arrhythmia after acute myocardial infarction through vagal afferent nerves. Reviewed International journal

    Yuanjie Mao, Takeshi Tokudome, Kentaro Otani, Ichiro Kishimoto, Michio Nakanishi, Hiroshi Hosoda, Mikiya Miyazato, Kenji Kangawa

    Endocrinology   153 ( 7 )   3426 - 34   2012.7

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    DOI： 10.1210/en.2012-1065

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  • Natriuretic peptide receptor guanylyl cyclase-A protects podocytes from aldosterone-induced glomerular injury. Reviewed International journal

    Yoshihisa Ogawa, Masashi Mukoyama, Hideki Yokoi, Masato Kasahara, Kiyoshi Mori, Yukiko Kato, Takashige Kuwabara, Hirotaka Imamaki, Tomoko Kawanishi, Kenichi Koga, Akira Ishii, Takeshi Tokudome, Ichiro Kishimoto, Akira Sugawara, Kazuwa Nakao

    Journal of the American Society of Nephrology : JASN   23 ( 7 )   1198 - 209   2012.7

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    DOI： 10.1681/ASN.2011100985

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  • One dose of ghrelin prevents the acute and sustained increase in cardiac sympathetic tone after myocardial infarction. Reviewed International journal

    Daryl O Schwenke, Takeshi Tokudome, Ichiro Kishimoto, Takeshi Horio, Patricia A Cragg, Mikiyasu Shirai, Kenji Kangawa

    Endocrinology   153 ( 5 )   2436 - 43   2012.5

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    DOI： 10.1210/en.2011-2057

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  • The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice. Reviewed International journal

    Shigetomo Fukuhara, Szandor Simmons, Shunsuke Kawamura, Asuka Inoue, Yasuko Orba, Takeshi Tokudome, Yuji Sunden, Yuji Arai, Kazumasa Moriwaki, Junji Ishida, Akiyoshi Uemura, Hiroshi Kiyonari, Takaya Abe, Akiyoshi Fukamizu, Masanori Hirashima, Hirofumi Sawa, Junken Aoki, Masaru Ishii, Naoki Mochizuki

    The Journal of clinical investigation   122 ( 4 )   1416 - 26   2012.4

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    DOI： 10.1172/JCI60746

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  • Ghrelin and cardiovascular diseases. Reviewed International journal

    Ichiro Kishimoto, Takeshi Tokudome, Hiroshi Hosoda, Mikiya Miyazato, Kenji Kangawa

    Journal of cardiology   59 ( 1 )   8 - 13   2012.1

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    DOI： 10.1016/j.jjcc.2011.11.002

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  • 血管恒常性維持におけるANP・BNPの多彩な生理作用

    徳留 健, 大谷 健太郎, 岸本 一郎, 新藤 隆行, 小山 晃英, 白井 幹康, 堀尾 武史, 河野 雄平, 中尾 一和, 寒川 賢治

    日本内分泌学会雑誌   87 ( 2 )   777 - 777   2011.9

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  • Centrally administered ghrelin activates cardiac vagal nerve in anesthetized rabbits. Reviewed International journal

    Shuji Shimizu, Tsuyoshi Akiyama, Toru Kawada, Takashi Sonobe, Atsunori Kamiya, Toshiaki Shishido, Takeshi Tokudome, Hiroshi Hosoda, Mikiyasu Shirai, Kenji Kangawa, Masaru Sugimachi

    Autonomic neuroscience : basic & clinical   162 ( 1-2 )   60 - 5   2011.7

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    DOI： 10.1016/j.autneu.2011.04.001

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  • Natriuretic peptide system: an overview of studies using genetically engineered animal models. Reviewed International journal

    Ichiro Kishimoto, Takeshi Tokudome, Kazuwa Nakao, Kenji Kangawa

    The FEBS journal   278 ( 11 )   1830 - 41   2011.6

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    DOI： 10.1111/j.1742-4658.2011.08116.x

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  • Interleukin-6 as an independent predictor of future cardiovascular events in high-risk Japanese patients: comparison with C-reactive protein. Reviewed International journal

    Hidenori Nishida, Takeshi Horio, Yoshihiko Suzuki, Yoshio Iwashima, Takeshi Tokudome, Fumiki Yoshihara, Satoko Nakamura, Yuhei Kawano

    Cytokine   53 ( 3 )   342 - 6   2011.3

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    DOI： 10.1016/j.cyto.2010.12.005

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  • The Role of the Natriuretic Peptide System in Metabolic Syndrome and Related Kidney Diseases Reviewed

    Kishimoto Ichiro, Makino Hisashi, Yoshihara Fumiki, Sugisawa Takako, Yoshimasa Yasunao, Kokubo Yoshihiro, Nakao Kazuwa, Tokudome Takeshi, Kangawa Kenji

    CLINICAL AND EXPERIMENTAL HYPERTENSION   33 ( 1 )   4   2011

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  • Chronic kidney disease as an independent risk factor for new-onset atrial fibrillation in hypertensive patients. Reviewed International journal

    Takeshi Horio, Yoshio Iwashima, Kei Kamide, Takeshi Tokudome, Fumiki Yoshihara, Satoko Nakamura, Yuhei Kawano

    Journal of hypertension   28 ( 8 )   1738 - 44   2010.8

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    DOI： 10.1097/HJH.0b013e32833a7dfe

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  • Additive interaction of metabolic syndrome and chronic kidney disease on cardiac hypertrophy, and risk of cardiovascular disease in hypertension. Reviewed International journal

    Yoshio Iwashima, Takeshi Horio, Kei Kamide, Takeshi Tokudome, Fumiki Yoshihara, Satoko Nakamura, Toshio Ogihara, Hiromi Rakugi, Yuhei Kawano

    American journal of hypertension   23 ( 3 )   290 - 8   2010.3

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    DOI： 10.1038/ajh.2009.253

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  • 内因性ANP・BNPによる血管新生、血管恒常性維持機構

    徳留 健, 岸本 一郎, 新藤 隆行, 川上 速人, 小山 晃英, 中尾 一和, 寒川 賢治

    血管   33 ( 1 )   14 - 14   2010.1

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  • Association of insulin-like growth factor-1 receptor gene polymorphisms with left ventricular mass and geometry in essential hypertension. Reviewed

    Horio T, Kamide K, Takiuchi S, Yoshii M, Miwa Y, Matayoshi T, Yoshihara F, Nakamura S, Tokudome T, Miyata T, Kawano Y

    J Hum Hypertens.   24   320 - 326   2010

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  • Impaired recovery of blood flow after hind-limb ischemia in mice lacking guanylyl cyclase-A, a receptor for atrial and brain natriuretic peptides. Reviewed International journal

    Takeshi Tokudome, Ichiro Kishimoto, Kenichi Yamahara, Tsukasa Osaki, Naoto Minamino, Takeshi Horio, Kazutomo Sawai, Yuhei Kawano, Mikiya Miyazato, Masataka Sata, Masakazu Kohno, Kazuwa Nakao, Kenji Kangawa

    Arteriosclerosis, thrombosis, and vascular biology   29 ( 10 )   1516 - 21   2009.10

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    DOI： 10.1161/ATVBAHA.109.187526

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  • Therapeutic potential of ghrelin in cardiac diseases. Reviewed International journal

    Ichiro Kishimoto, Takeshi Tokudome, Daryl O Schwenke, Soeki Takeshi, Hiroshi Hosoda, Noritoshi Nagaya, Kenji Kangawa

    Expert review of endocrinology & metabolism   4 ( 3 )   283 - 289   2009.5

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    DOI： 10.1586/eem.09.7

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  • Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart. Reviewed International journal

    Ichiro Kishimoto, Takeshi Tokudome, Takeshi Horio, David L Garbers, Kazuwa Nakao, Kenji Kangawa

    Current cardiology reviews   5 ( 1 )   45 - 51   2009.1

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    DOI： 10.2174/157340309787048068

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  • C-Type Natriuretic Peptide is a Schwann Cell-Derived Factor For Development and Function of Sensory Neurones Reviewed

    I. Kishimoto, T. Tokudome, T. Horio, T. Soeki, H. Chusho, K. Nakao, K. Kangawa

    JOURNAL OF NEUROENDOCRINOLOGY   20 ( 11 )   1213 - 1223   2008.11

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    DOI： 10.1111/j.1365-2826.2008.01778.x

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  • Early ghrelin treatment after myocardial infarction prevents an increase in cardiac sympathetic tone and reduces mortality. Reviewed International journal

    Daryl O Schwenke, Takeshi Tokudome, Ichiro Kishimoto, Takeshi Horio, Mikiyasu Shirai, Patricia A Cragg, Kenji Kangawa

    Endocrinology   149 ( 10 )   5172 - 6   2008.10

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    DOI： 10.1210/en.2008-0472

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  • Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Reviewed International journal

    Takeshi Tokudome, Ichiro Kishimoto, Takeshi Horio, Yuji Arai, Daryl O Schwenke, Jun Hino, Ichiro Okano, Yuhei Kawano, Masakazu Kohno, Mikiya Miyazato, Kazuwa Nakao, Kenji Kangawa

    Circulation   117 ( 18 )   2329 - 39   2008.5

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    DOI： 10.1161/CIRCULATIONAHA.107.732990

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  • Exogenous ghrelin attenuates the progression of chronic hypoxia-induced pulmonary hypertension in conscious rats. Reviewed International journal

    Daryl O Schwenke, Takeshi Tokudome, Mikiyasu Shirai, Hiroshi Hosoda, Takeshi Horio, Ichiro Kishimoto, Kenji Kangawa

    Endocrinology   149 ( 1 )   237 - 44   2008.1

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    DOI： 10.1210/en.2007-0833

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  • Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Reviewed International journal

    Takeshi Soeki, Ichiro Kishimoto, Daryl O Schwenke, Takeshi Tokudome, Takeshi Horio, Morikatsu Yoshida, Hiroshi Hosoda, Kenji Kangawa

    American journal of physiology. Heart and circulatory physiology   294 ( 1 )   H426-32 - H432   2008.1

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    DOI： 10.1152/ajpheart.00643.2007

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  • [Cardioprotective effects of natriuretic peptides]. Reviewed

    Takeshi Tokudome, Ichiro Kishimoto, Takeshi Horio, Kenji Kangawa

    Nihon rinsho. Japanese journal of clinical medicine   65 Suppl 4   165 - 9   2007.4

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  • Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Reviewed International journal

    Noritoshi Nagaya, Kenji Kangawa, Takefumi Itoh, Takashi Iwase, Shinsuke Murakami, Yoshinori Miyahara, Takafumi Fujii, Masaaki Uematsu, Hajime Ohgushi, Masakazu Yamagishi, Takeshi Tokudome, Hidezo Mori, Kunio Miyatake, Soichiro Kitamura

    Circulation   112 ( 8 )   1128 - 35   2005.8

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    DOI： 10.1161/CIRCULATIONAHA.104.500447

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  • Calcineurin-nuclear factor of activated T cells pathway-dependent cardiac remodeling in mice deficient in guanylyl cyclase A, a receptor for atrial and brain natriuretic peptides. Reviewed International journal

    Takeshi Tokudome, Takeshi Horio, Ichiro Kishimoto, Takeshi Soeki, Kenji Mori, Yuhei Kawano, Masakazu Kohno, David L Garbers, Kazuwa Nakao, Kenji Kangawa

    Circulation   111 ( 23 )   3095 - 104   2005.6

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    DOI： 10.1161/CIRCULATIONAHA.104.510594

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  • Chronic administration of adrenomedullin attenuates the hypertension and increases renal nitric oxide synthase in Dahl salt-sensitive rats. Reviewed International journal

    Fumiki Yoshihara, Shin-ichi Suga, Naomi Yasui, Takeshi Horio, Takeshi Tokudome, Toshio Nishikimi, Yuhei Kawano, Kenji Kangawa

    Regulatory peptides   128 ( 1 )   7 - 13   2005.5

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    DOI： 10.1016/j.regpep.2004.12.028

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  • Upregulation of intracardiac adrenomedullin and its receptor system in rats with volume overload-induced cardiac hypertrophy. Reviewed International journal

    Fumiki Yoshihara, Toshio Nishikimi, Ichiro Okano, Jun Hino, Takeshi Horio, Takeshi Tokudome, Shin-ichi Suga, Hiroaki Matsuoka, Kenji Kangawa, Yuhei Kawano

    Regulatory peptides   127 ( 1-3 )   239 - 44   2005.4

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    DOI： 10.1016/j.regpep.2004.12.017

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  • C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction. Reviewed International journal

    Takeshi Soeki, Ichiro Kishimoto, Hiroyuki Okumura, Takeshi Tokudome, Takeshi Horio, Kenji Mori, Kenji Kangawa

    Journal of the American College of Cardiology   45 ( 4 )   608 - 16   2005.2

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    DOI： 10.1016/j.jacc.2004.10.067

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  • Production and autocrine/paracrine effects of endogenous insulin-like growth factor-1 in rat cardiac fibroblasts. Reviewed International journal

    Takeshi Horio, Toshiyuki Maki, Ichiro Kishimoto, Takeshi Tokudome, Hiroyuki Okumura, Fumiki Yoshihara, Shin-ichi Suga, Satoshi Takeo, Yuhei Kawano, Kenji Kangawa

    Regulatory peptides   124 ( 1-3 )   65 - 72   2005.1

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    DOI： 10.1016/j.regpep.2004.06.029

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  • Direct effects of high glucose and insulin on protein synthesis in cultured cardiac myocytes and DNA and collagen synthesis in cardiac fibroblasts. Reviewed International journal

    Takeshi Tokudome, Takeshi Horio, Fumiki Yoshihara, Shin-Ichi Suga, Yuhei Kawano, Masakazu Kohno, Kenji Kangawa

    Metabolism: clinical and experimental   53 ( 6 )   710 - 5   2004.6

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    DOI： 10.1016/j.metabol.2004.01.006

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  • Inhibitory effect of C-type natriuretic peptide (CNP) on cultured cardiac myocyte hypertrophy: interference between CNP and endothelin-1 signaling pathways. Reviewed International journal

    Takeshi Tokudome, Takeshi Horio, Takeshi Soeki, Kenji Mori, Ichiro Kishimoto, Shin-ichi Suga, Fumiki Yoshihara, Yuhei Kawano, Masakazu Kohno, Kenji Kangawa

    Endocrinology   145 ( 5 )   2131 - 40   2004.5

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    DOI： 10.1210/en.2003-1260

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  • Ventricular nonmyocytes inhibit doxorubicin-induced myocyte apoptosis: involvement of endogenous endothelin-1 as a paracrine factor. Reviewed International journal

    Takeshi Tokudome, Takeshi Horio, Megumu Fukunaga, Hiroyuki Okumura, Jun Hino, Kenji Mori, Fumiki Yoshihara, Shin-Ichi Suga, Yuhei Kawano, Masakazu Kohno, Kenji Kangawa

    Endocrinology   145 ( 5 )   2458 - 66   2004.5

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    DOI： 10.1210/en.2003-1322

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  • Gene expression, secretion, and autocrine action of C-type natriuretic peptide in cultured adult rat cardiac fibroblasts. Reviewed International journal

    Takeshi Horio, Takeshi Tokudome, Toshiyuki Maki, Fumiki Yoshihara, Shin-Ichi Suga, Toshio Nishikimi, Masayasu Kojima, Yuhei Kawano, Kenji Kangawa

    Endocrinology   144 ( 6 )   2279 - 84   2003.6

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    DOI： 10.1210/en.2003-0128

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  • Adrenomedullin inhibits doxorubicin-induced cultured rat cardiac myocyte apoptosis via a cAMP-dependent mechanism. Reviewed International journal

    Takeshi Tokudome, Takeshi Horio, Fumiki Yoshihara, Shin-Ichi Suga, Yuhei Kawano, Masakazu Kohno, Kenji Kangawa

    Endocrinology   143 ( 9 )   3515 - 21   2002.9

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    DOI： 10.1210/en.2002-220233

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  • Sensitive detection of myocardial contraction abnormality in chronic hemodialysis patients by ultrasonic tissue characterization with integrated backscatter Reviewed

    K Mizushige, T Tokudome, M Seki, Kondo, I, K Hirao, S Nozaki, S Miki, S Yuasa, H Matsuo

    ANGIOLOGY   51 ( 3 )   223 - 230   2000.3

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  • ポドサイト特異的p38 MAPK & GC-Aダブルノックアウトマウスの腎病変におけるポドサイト-内皮連関の解明

    杉岡 清香, 山田 博之, 加藤 有希子, 石井 輝, 森 慶太, 大崎 啓介, 徳留 健, 松阪 泰二, 柳田 素子, 横井 秀基

    日本腎臓学会誌   64 ( 3 )   226 - 226   2022.5

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  • モデル動物を用いた周産期心筋症発症機序の解明

    大谷 健太郎, 徳留 健, 神谷 千津子, 池田 智明

    日本心臓病学会学術集会抄録   67回   SS - 4   2019.9

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  • Endothelium-derived C-type natriuretic peptide regulates blood pressure through the maintenance of endothelial function

    K. Kuwahara, K. Nakao, T. Nishikimi, Y. Nakagawa, H. Kinoshita, T. Tokudome, N. Minamino, T. Kimura, K. Kangawa, K. Nakao

    EUROPEAN JOURNAL OF HEART FAILURE   19   596 - 596   2017.5

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  • アルドステロン投与下のGC‐AノックアウトマウスにおけるMMP‐10の意義

    大崎啓介, 加藤有希子, 戸田尚宏, 石井輝, 森潔, 徳留健, 松阪泰二, 向山政志, 柳田素子, 横井秀基

    日本腎臓学会誌   59 ( 3 )   306 - 306   2017.4

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  • ROLE OF THE NATRIURETIC PEPTIDE-A RECEPTOR ON PODOCYTES IN ALDOSTERONE-INDUCED GLOMERULAR INJURY

    Hideki Yokoi, Yukiko Kato, Kiyoshi Mori, Masato Kasahara, Keisuke Osaki, Takashige Kuwabara, Taiji Mastsusaka, Takeshi Tokudome, Kazuwa Nakao, Motoko Yanagita, Masashi Mukoyama

    JOURNAL OF HYPERTENSION   34   E258 - E258   2016.9

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    DOI： 10.1097/01.hjh.0000500588.80565.13

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  • Preventive effect of renin-angiotensin system inhibitors on new-onset atrial fibrillation in hypertensive patients: a propensity score matching analysis

    T. Horio, M. Akiyama, Y. Iwashima, F. Yoshihara, S. Nakamura, T. Tokudome, I. Komatsubara, N. Okimoto, S. Kamakura, Y. Kawano

    EUROPEAN HEART JOURNAL   37   13 - 14   2016.8

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  • Atrial Natriuretic Peptide Attenuates Bleomycin-Induced Pulmonary Fibrosis In Mice

    A. Okamoto, K. Konishi, T. Nojiri, H. Hosoda, T. Tokudome, K. Asai, K. Hirata, K. Kangawa

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   193   2016

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  • Translational research of ghrelin in cardiovascular and metabolic diseases

    47 ( 7 )   352 - 355   2015.7

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  • ポドサイトにおけるNa利尿ペプチドGC‐A受容体のp38MAPK阻害を介した腎保護作用

    加藤有希子, 横井秀基, 森潔, 笠原正登, 小川喜久, 桑原孝成, 徳留健, 岸本一郎, 菅原照, 松阪泰二, 中尾一和, 柳田素子, 向山政志

    日本腎臓学会誌   57 ( 3 )   478   2015.4

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  • Defective Cardiac Natriuretic Peptide Signaling Leads to Lactation-induced Postpartum Cardiomyopathy

    Kentaro Otani, Takeshi Tokudome, Ichiro Kishimoto, Yuanjie Mao, Kenichi Yamahara, Kenji Kangawa, Tomoaki Ikeda

    CIRCULATION   126 ( 21 )   2012.11

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  • Combination Therapy with Renin-Angiotensin System Inhibitors and Statins is Associated with Reduced Incidence of New-Onset Atrial Fibrillation in Hypertensive Patients

    Takeshi Horio, Yoshio Iwashima, Takeshi Tokudome, Fumiki Yoshihara, Satoko Nakamura, Maki Akiyama, Satoshi Nishimura, Mikumo Sakaguchi, Yuhei Kawano

    CIRCULATION   126 ( 21 )   2012.11

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  • 高血圧患者におけるアムロジピンまたはロサルタンによる家庭血圧の厳格あるいは緩和な降圧が頸動脈内中膜厚の進展に及ぼす影響 HOSPサブスタディ

    大田 祐子, 岩嶋 義雄, 林 真一郎, 堀尾 武史, 神出 計, 滝内 伸, 徳留 健, 吉原 史樹, 中村 敏子, 河野 雄平

    日本高血圧学会総会プログラム・抄録集   35回   422 - 422   2012.9

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  • Reduced Incidence of New-Onset Atrial Fibrillation With Renin-Angiotensin System Inhibitors in Japanese Hypertensive Patients

    Takeshi Horio, Yoshio Iwashima, Kei Kamide, Takeshi Tokudome, Fumiki Yoshihara, Satoko Nakamura, Maki Akiyama, Satoshi Nishimura, Yuhei Kawano

    CIRCULATION   124 ( 21 )   2011.11

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  • 内因性ナトリウム利尿ペプチドの虚血組織血管新生促進作用

    徳留 健, 岸本 一郎, 寒川 賢治

    治療   93 ( 4 )   686 - 688   2011.4

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    Other Link： http://search.jamas.or.jp/link/ui/2011187757

  • Centrally Administered Ghrelin Enhances Acetylcholine Release from Cardiac Vagal Nerve Endings

    Shuji Shimizu, Tsuyoshi Akiyama, Toru Kawada, Takashi Sonobe, Atsunori Kamiya, Toshiaki Shishido, Takeshi Tokudome, Hiroshi Hosoda, Mikiyasu Shirai, Kenji Kangawa, Masaru Sugimachi

    CIRCULATION   122 ( 21 )   2010.11

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  • SPring-8高輝度放射光を用いた小動物の心臓・血管機能の画像解析

    白井 幹康, Pearson James, Schwenke Daryl, 曽野部 崇, 藤井 豊, 吉本 光佐, 徳留 健, 清水 壽一郎, 寒川 賢治, 梅谷 啓二, 八木 直人

    循環器病研究の進歩   XXXI ( 1 )   68 - 80   2010.11

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  • 内因性ANP・BNPによる血管新生、血管恒常性維持機構

    徳留 健, 岸本 一郎, 山原 研一, 新藤 隆行, 川上 速人, 白井 幹康, 寒川 賢治

    血管   33 ( 3 )   75 - 80   2010.10

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    心房性・脳性ナトリウム利尿ペプチド(ANP・BNP)の共通受容体であるguanylyl cyclase-A(GC-A)の遺伝子欠損マウス(GC-A-KO)に下肢虚血モデルを作成し、野生型マウスとの間で血流回復・血管新生について比較検討した。GC-A-KOマウスでは下肢虚血組織における血管新生が、野生型マウスに比較して顕著に抑制され、下肢虚血組織において、GC-Aの遺伝子発現が増加し、骨髄由来のEPCsにもGC-Aは発現しており、虚血組織における血管新生に関与していることを証明した。また、ANPは培養血管内皮細胞において、eNOSおよびVEGFの遺伝子発現をERKの活性化を介して亢進させた。虚血組織局所のGC-Aが血管新生において重要な役割を担っていることが示唆された。また、EPCsに発現しているGC-Aも、虚血組織における血管新生に関与していた。

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  • 日本人高血圧患者におけるRA系阻害薬の心房細動新規発症抑制効果を検証する

    堀尾 武史, 岩嶋 義雄, 神出 計, 徳留 健, 高田 英明, 藤井 健, 吉原 史樹, 中村 敏子, 河野 雄平

    日本高血圧学会総会プログラム・抄録集   33回   242 - 242   2010.10

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  • 妊産婦と循環器疾患 心血管疾患合併妊娠、周産期(産褥)心筋症のup to date

    池田 智明, 神谷 千津子, 大谷 健太郎, 徳留 健, 岸本 一郎

    日本心臓病学会誌   5 ( Suppl.I )   198 - 198   2010.8

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  • Important Roles of Endogenous Atrial and Brain Natriuretic Peptides in Reparative Vascular Remodeling in Ischemic Tissue

    TOKUDOME Takeshi, KISHIMOTO Ichiro, KANGAWA Kenji

    50 ( 2 )   169 - 174   2010.4

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  • 内因性ANP,BNPの血管新生における新たな意義

    徳留健, 岸本一郎, 新藤隆行, 山原研一, 尾崎司, 南野直人, 堀尾武史, 澤井一智, 佐田政隆, 河野雅和, 中尾一和, 寒川賢治

    日本内分泌学会雑誌   86 ( 1 )   142 - 142   2010.3

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  • Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart

    Takeshi Tokudome, Ichiro Kishimoto, Kazuwa Nakao, Kenji Kangawa

    ENDOCRINE JOURNAL   57   S325 - S325   2010.3

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  • Lack of natriuretic peptide action aggravates insulin resistance and hypertension linked to diet-induced obesity in mice

    Hisashi Makino, Takeshi Tokudome, Ichiro Kishimoto, Yoshihiro Miyamoto, Yuhei Kawano, Kazuwa Nakao, Yasunao Yoshimasa, Kenji Kangawa

    ENDOCRINE JOURNAL   57   S551 - S551   2010.3

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  • The therapeutic potential of ghrelin in cardiac diseases-The role of peripheral nerve

    Ichiro Kishimoto, Takeshi Tokudome, Daryl Schwenke, Takeshi Soeki, Noritoshi Nagaya, Kenji Kangawa

    ENDOCRINE JOURNAL   57   S446 - S446   2010.3

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  • Impaired recovery of blood flow after hind-limb ischemia in mice lacking guanylyl cyclase-A, a receptor for atrial and brain natriuretic peptides

    Takeshi Tokudome, Ichiro Kishimoto, Kazuwa Nakao, Kenji Kangawa

    ENDOCRINE JOURNAL   57   S338 - S338   2010.3

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  • The cardiac natriuretic peptides/guanylyl cyclase-A signaling pathway in cardiovascular/metabolic diseases

    Ichiro Kishimoto, Takeshi Tokudome, Hisashi Makino, Takako Sugisawa, Yoshihiro Miyamoto, Kenichi Yamahara, Kazuwa Nakao, Kenji Kangawa

    ENDOCRINE JOURNAL   57   S270 - S270   2010.3

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  • The role of C-type natriuretic peptide in development and function of peripheral sensory neurons

    Ichiro Kishimoto, Takeshi Tokudome, Hideki Chusho, Naohisa Tamura, Kazuwa Nakao, Kenji Kangawa

    ENDOCRINE JOURNAL   57   S446 - S446   2010.3

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  • Early ghrelin treatment following myocardial infarction prevents an increase in cardiac sympathetic tone and reduces mortality

    Mikiyasu Shirai, Schwenke Daryl, Takeshi Tokudome, Ichiro Kishimoto, Kenji Kangawa

    JOURNAL OF PHYSIOLOGICAL SCIENCES   60   S164 - S164   2010

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  • Postchallenge Hyperglycemia is an Independent Risk Factor for Left Ventricular Hypertrophy in Non-diabetic Hypertensive Patients

    Takeshi Horio, Yoshio Iwashima, Fumiki Yoshihara, Satoko Nakamura, Takeshi Tokudome, Yuhei Kawano

    CIRCULATION   120 ( 18 )   S1163 - S1163   2009.11

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  • 降圧治療中の外来高血圧患者におけるJSH2009ガイドライン基準により評価した外来および家庭血圧の降圧目標到達率

    堀尾 武史, 岩嶋 義雄, 吉原 史樹, 中村 敏子, 徳留 健, 神出 計, 河野 雄平

    日本高血圧学会総会プログラム・抄録集   32回   198 - 198   2009.10

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  • 内因性ANP、BNPの血管新生作用に関する検討

    徳留 健, 岸本 一郎, 山原 研一, 堀尾 武史, 澤井 一智, 佐田 政隆, 河野 雅和, 中尾 一和, 寒川 賢治

    血管   32 ( 1 )   21 - 21   2009.1

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  • Chronic Kidney Disease as an Independent Risk Factor for New-Onset Atrial Fibrillation in Patients with Essential Hypertension

    Takeshi Horio, Yoshio Iwashima, Kei Kamide, Takeshi Tokudome, Hiroto Nakata, Fumiki Yoshihara, Satoko Nakamura, Hajime Nakahama, Yuhei Kawano

    CIRCULATION   118 ( 18 )   S727 - S728   2008.10

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  • 高血圧患者における心房細動新規発症に対する独立危険因子としての慢性腎臓病(CKD)

    堀尾 武史, 岩嶋 義雄, 神出 計, 徳留 健, 中田 裕人, 吉原 史樹, 中村 敏子, 中濱 肇, 河野 雄平

    日本高血圧学会総会プログラム・抄録集   31回   162 - 162   2008.10

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  • Exogenous ghrelin suppresses cardiac sympathetic tone following acute myocardial infarct in rats

    Daryl Owen Schwenke, Takeshi Tokudome, Ichiro Kishimoto, Patricia Cragg, Kenji Kangawa

    FASEB JOURNAL   22   2008.4

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  • The Significance of Ghrelin in the Cardiovascular Diseases

    I. Kishimto, T. Soeki, D. Schwenke, H. Hosoda, T. Tokudome, N. Nagaya, K. Kangawa

    CLINICAL AND EXPERIMENTAL HYPERTENSION   30 ( 6 )   439 - 439   2008

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  • Ghrelin suppresses cardiac sympathetic activity and attenuates early left ventricular remodeling in rats with myocardial infarction

    T Soeki, Kishimoto, I, H Hosoda, M Yoshida, T Tokudome, T Horio, D Schwenke, K Kangawa, S Ito

    CIRCULATION   112 ( 17 )   U90 - U90   2005.10

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  • メタボリックシンドロームと高血圧性心変化 治療下本態性高血圧症例における検討

    堀尾 武史, 神出 計, 吉原 史樹, 中村 敏子, 中濱 肇, 中田 裕人, 又吉 哲太郎, 新妻 晋一郎, 加藤 とあこ, 徳留 健, 河野 雄平

    日本高血圧学会総会プログラム・抄録集   28回   169 - 169   2005.9

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  • Ghrelin Suppresses Cardiac Sympathetic Activity and Attenuates Early Left Ventricular Remodeling in Rats with Myocardial Infarction(Old Myocardial Infarction/Remodeling 1 (IHD), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

    Soeki Takeshi, Kishimoto Ichirou, Hosoda Hiroshi, Yoshida Morikatsu, Tokudome Takeshi, Horio Takeshi, Schwenke Daryl, Pearson James, Shirai Mikiyasu, Kangawa Kenji

    Circulation journal : official journal of the Japanese Circulation Society   69   274 - 274   2005.3

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  • C-type natriuretic peptide, a novel antifibrotic agent, attenuates cardiac remodeling and improves left ventricular dysfunction in dilated cardiomyopathy

    T Soeki, Kishimoto, I, T Tokudome, T Horio, K Kangawa

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   45 ( 3 )   420A - 420A   2005.2

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  • OE-361 Inhibitory Effect of C-Type Natriuretic Peptide (CNP) on Cultured Cardiac Myocyte Hypertrophy : Interference between CNP and Endothelin-1 Signaling Pathways(Cardiac Hypertrophy, Basic and Clinical 1 (M) : OE46)(Oral Presentation (English))

    Tokudome Takeshi, Horio Takeshi, Soeki Takeshi, Kishimoto Ichirou, Suga Shinichi, Yoshihara Fumiki, Kawano Yuhei, Kohno Masakazu, Kangawa Kenji

    Circulation journal : official journal of the Japanese Circulation Society   68   227 - 228   2004.3

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  • Chronic administration of adrenomedullin improves pressure-natriuresis relationship and increases renal neuronal nitric oxide synthase in Dahl salt-sensitive rats

    F Yoshihara, S Suga, H Nakahama, N Yasui, T Horio, T Tokudome, T Nishikimi, S Nakamura, T Inenaga, Y Kawano, K Kangawa

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   14   139A - 139A   2003.11

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  • Endogenous Endothelin-1 Secreted from Cultured Rat Cardiac Nonmyocytes Inhibits Doxorubicin-Induced Cardiac Myocyte Apoptosis via ERK-Dependent CREB Activation

    Tokudome Takeshi, Horio Takeshi, Suga Shinichi, Kishimoto Ichiro, Hino Jun, Okano Ichiro, Mori Kenji, Yoshihara Fumiki, Kawano Yuhei, Kohno Masakazu, Kangawa Kenji

    Circulation journal : official journal of the Japanese Circulation Society   67   126 - 126   2003.3

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  • Gene expression, secretion, and autocrine effect of C-type natriuretic peptide in cultured adult rat cardiac fibroblasts

    T Horio, T Maki, F Yoshihara, T Tokudome, SI Suga, Y Kawano, K Kangawa

    CIRCULATION   104 ( 17 )   307 - 307   2001.10

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  • Inhibitory effect of C-type natriuretic peptide (CNP) on cultured cardiac myocyte hypertrophy : interference between CNP and endothelin-1 signaling pathways

    TOKUDOME T

    Endocrinology   145 ( 5 )   2131 - 2140   2001

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  • Prevention of doxorubicin (adriamycin)-induced cardiomyopathy by simultaneous administration of angiotensin-converting enzyme inhibitor assessed by acoustic densitometry

    TOKUDOME T.

    J Cardiovasc Pharmacol   36   361 - 368   2000

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  • Neurogenic regulation of basal tone of coronary artery with mild atherosclerosis in humans: Observation using two-dimensional intravascular ultrasound

    T Tokudome, K Mizushige, K Ohmori, K Watanabe, Y Takagi, Y Takano, H Matsuo

    ANGIOLOGY   50 ( 12 )   989 - 996   1999.12

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  • Effect of disopyramide on left ventricular pressure gradient in hypertrophic obstructive cardiomyopathy in comparison with propranolol - A case report

    T Tokudome, K Mizushige, T Ueda, S Sakamoto, H Matsuo

    ANGIOLOGY   50 ( 4 )   331 - 335   1999.4

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Awards

  • 成人血管病研究振興財団岡本研究奨励賞

    徳留 健

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  • 高峰譲吉研究奨励賞

    徳留 健

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  • 日本循環器学会Young Investigator's Award最優秀賞

    徳留 健

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  • 日本心脈管作動物質学会研究奨励賞

    徳留 健

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  • 日本心不全学会Young Investigator's Award優秀賞

    徳留 健

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  • 日本脈管学会Young Investigator's Award最優秀賞

    徳留 健

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  • 高血圧関連疾患モデル学会優秀演題賞

    徳留 健

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  • 日本心血管内分泌代謝学会若手研究奨励賞

    徳留 健

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Research Projects

  • 抗インターロイキン-6 受容体抗体のドラッグリポジショニングで心筋炎症を抑制する、周産期心筋症の新規治療法の開発と治験の準備

    2022.4 - 2025.3

    日本医療研究開発機構（AMED）  令和4年度 難治性疾患実用化研究事業 

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    Authorship：Coinvestigator(s) 

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  • 周産期心筋症の病態－遺伝要因・心筋炎症・血管障害－解明研究

    Grant number：21K08043  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    神谷 千津子, 徳留 健, 大谷 健太郎, 吉松 淳, 高橋 篤

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    周産期心筋症は、心筋疾患既往のない女性が、妊娠中から産後にかけて心収縮機能の低下と心不全を発症する、特異な心筋症である。日本における発症率は、推定約1.5万分娩に1例と高くはないが、母体間接死亡原因の上位疾患に挙げられる。本研究者は、全国質問紙調査（平成21年）を端緒に、全国多施設患者レジストリを創出し、当該疾患の臨床－基礎研究を継続して行ってきた。これまでの研究蓄積から、周産期心筋症の病態として、①遺伝要因、②心筋炎症、③血管障害の三要素が挙げられる。そこで、本研究では、臨床情報・試料（集積済）を用いて、これら三要素について心機能予後との関連をより詳しく解析することを目的とする。
    令和3年度は、①について、アメリカ、ドイツとの国際共同により、周産期心筋症と診断された469人の女性を対象に、心筋症関連67遺伝子について次世代シーケンサーによる解析・報告を行った（Circulation 2021）。10.4%に心筋サルコメア蛋白であるタイチン遺伝子のtruncating variants(TTNtvs)を認めた。他に、FLNC、DSP、BAG3のtruncating variantsを認め、これらの関連遺伝子のloss-of-function variants発現率は、特発性拡張型心筋症コホートとほぼ相同であった。バリアントの有無と臨床像の比較検討においては、TTNtv陽性患者の診断時の心機能は、非陽性患者よりも有意に低かった。一方、診断時期、妊娠高血圧症候群の合併率、心機能回復率は、陽性患者と陰性患者で同等であった。本研究結果から、周産期心筋症患者も拡張型心筋症患者と同様に遺伝カウンセリングと遺伝子検査、結果に基づいた診療方針の適応が考慮される。

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  • グレリンの生理作用を応用した「抗癌剤誘発性心筋症」に対する画期的治療法開発

    Grant number：20K08505  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    徳留 健

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    当初の予定に基づき、ドキソルビシン誘発性心筋症モデルに対するグレリンの効果を調べる為、まずはマウスドキソルビシン誘発性心筋症モデルの確立に取り組んだ。13週齢野生型マウス(C57BL/6J)に、生理食塩水に溶解したドキソルビシン5mg/kgを週1回、合計5回投与した(n=20)。対照群には生理食塩水を投与した(n=10)。投与経路は腹腔内注射で、1回投与量は200μlであった。投与終了後、4週間の観察期間をもうけ、その後心エコーにて心機能評価を行った。注射時には毎回体重測定を行った。生理食塩水群では、投与開始時の体重が平均27.02gであり、ドキソルビシン群では平均27.21gであった。投与終了時の体重は、生理食塩水群では平均29.23g、ドキソルビシン群では25.80gであり、やはり有意にドキソルビシン群で体重が軽かった。観察期間終了時の体重は、生理食塩水群では平均31.12g、ドキソルビシン群では25.83gであり、有意にドキソルビシン群で体重が軽かった。投与中および観察期間中に死亡したマウスはいなかった。イソフルラン吸入麻酔下で行った心エコーの結果、左室内径短縮率には二群間で有意差を認めず、左室拡張末期径・左室収縮末期径・左室壁厚にも有意差を認めなかった。既報論文では今回の投与量よりも少ない量で一部のマウスが死亡し、左室機能が低下したといった結果が報告されているが、今回得た結果はそれらと異なるものであった。既報論文との違いの原因は定かではないが、ドキソルビシン投与で確実に体重が減っており、投与手法に問題は無いと考えている。今後投与するドキソルビシンの量を増やし、再度体重測定・心エコーを行う予定である。

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

    Grant number：17K09897  2017.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Tokudome Takeshi

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    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.

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  • Development of novel therapy for postpartum cardiomyopathy based on the comprehensive analysis of animal model and clinical gene sample

    Grant number：17K09543  2017.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    OTANI KENTARO

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    In our previous work, we demonstrated that mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and brain natriuretic peptides, show severe postpartum cardiac hypertrophy and dysfunction similar to postpartum cardiomyopathy (PPCM). Additionally, two weeks of lactation significantly increased the plasma aldosterone level in GC-A-knockout mice (GC-A-KO), but not in wild-type mice. Here, we examined the mechanisms underlying the lactation-induced and aldosterone-dependent cardiac hypertrophy in GC-A-KO. In GC-A-KO heart, the IL-6 mRNA level was significantly upregulated during lactation. Additionally, weekly intraperitoneal injection of anti-IL-6 receptor antibody tended to suppress the lactation-induced cardiac hypertrophy in GC-A-KO. Taken together, our data implied that natriuretic peptides, aldosterone receptor antagonist, and anti-interleukin-6 receptor antibody have potential to be therapeutic agents for PPCM.

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  • Development of a novel therapy for peripartum cardiomyopathy using natriuretic peptides

    Grant number：26461100  2014.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    OTANI KENTARO, KAMIYA CHIZUKO, NISHIMURA HIROHITO

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    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

    In recent work, we demonstrated that mice lacking guanylyl cyclase-A (GC-A-KO), a receptor for atrial and brain natriuretic peptides, show severe postpartum cardiac hypertrophy. Interestingly, the postpartum cardiac hypertrophy in GC-A-KO was induced during lactation. The aim was to investigate the mechanisms underlying the lactation-induced cardiac hypertrophy in GC-A-KO. Additionally, we examined the single-nucleotide polymorphisms of natriuretic peptide-related genes in patients with peripatrum cardiomyopathy (PPCM). Plasma aldosterone level was significantly elevated in lactating GC-A-KO. Furthermore, the administration of a specific mineralocorticoid receptor blocker during lactation significantly suppressed the cardiac hypertrophy in GC-A-KO. Therefore, aldosterone would be a cause of lactation-induced cardiac hypertrophy in GC-A-KO. In addition, genotype distribution of natriuretic peptide clearance receptor gene differed markedly between women with PPCM and their controls.

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  • Development of new therapy of cardiac disease utilizing physiological effect of ghrelin

    Grant number：25461082  2013.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    TOKUDOME TAKESHI

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    Grant amount：\5070000 （ Direct Cost: \3900000 、 Indirect Cost：\1170000 ）

    Ghrelin is a food intake promotion peptide that was discovered in the stomach by the group of Kenji kangawa (Director General, National Cerebral and Cardiovascular Center Research Institute). We previously reported that ghrelin administration improves pathogenesis of myocardial infarction model. In the present study, we found that endogenous ghrelin improves pathogenesis of myocardial infarction and cardiac hypertrophy model, ghrelin protect the heart from remodeling after myocardial infarction and cardiac hypertrophy by inhibiting sympathetic nervous activity and activating parasympathetic nervous activity, and also ghrelin receptor agonist; hexarelin improves pathogenesis of myocardial infarction model. These findings suggest that not only ghrelin but also hexarelin can be a therapeutic agent of cardiac diseases.

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  • Translational Research of Ghrelin in Cardiometabolic Diseases and Its Potent Regulatory Role of Autonomic Nerve Function

    Grant number：24390204  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    KISHIMOTO Ichiro, TOKUDOME Takeshi, KANGAWA Kenji, AKAMIZU Takashi, SOEKI Takeshi

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    Grant amount：\17810000 （ Direct Cost: \13700000 、 Indirect Cost：\4110000 ）

    One bolus subcutaneous administration of ghrelin prevents arrhythmia and reduces mortality in the acute phase of myocardial infarction (MI), while continuous administration improves LV dysfunction and attenuates early cardiac remodeling after acute MI. The mechanism of ghrelin’s action is related to down-regulation of the cardiac sympathetic nerve activity (SNA).The detrimental effect of a lack of endogenous ghrelin on malignant arrhythmia within 30 minutes after MI were also demonstrated in mice deficient for ghrelin, which have deteriorated heart function and high mortality after MI. The underlying mechanism is associated with the impaired inhibition of cardiac sympathetic activation by ghrelin.These results suggest existance of the stomach-brain-heart axis.

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  • Basic Research toward Discovery for New Renal Treatment using Bioactive Peptides

    Grant number：22590906  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    YOSHIHARA Fumiki, TOKUDOME Takeshi

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    Chronic angiotensin II (Ang II) infusion promotes renal interstitial fibrosis. To evaluate the pathophysiological significance of the natriuretic peptide-GC-A system, we infused Ang II in GC-A-deficient mice (GC-A-KO) and wild mice. The natriuretic peptide-GC-A system may play an inhibitory role in Ang II-induced renal tubular atrophy, interstitial fibrosis, and phenotypic transformation in renal tubular cells and fibroblasts. Renal blood flow evaluated using microspheres was significantly lower in GC-A-KO mice than that in wild mice. The reduction of renal blood flow in GC-A-KO mice relative to that in wild mice may be one possibility for advanced renal tubular damage and interstitial fibrosis in Ang II-infused GC-A-KO.

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  • Development of new therapy of cardiovascular disease utilizing specificity of biologically active peptide hormones

    Grant number：22790891  2010 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    TOKUDOME Takeshi, SCHWENKE Daryl O., MAO Yuanjie

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    Grant amount：\4030000 （ Direct Cost: \3100000 、 Indirect Cost：\930000 ）

    We recently published that ghrelin(an orexigenic peptide) administration was able to improve malignant arrhythmia-induced mortality in acute myocardial infarction. The present study demonstrated that one dose of ghrelin improves death rate in acute phase and also prevents cardiac remodeling in myocardial infarction. Furthermore, also demonstrated that endogenous ghrelin suppressed arrhythmia-induced death through inhibition of sympathetic nerve activity and activation of parasympathetic nerve activity in acute myocardial infarcti on. These findings suggest potential usefulness of ghrelin as a therapeutic agent in myocardial infarction.

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  • The therapeutic potentials of ghrelin in cardiovascular diseases-roles of the autonomic nervous system

    Grant number：21390252  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    KISHIMOTO Ichiro, TOKUDOME Takeshi, KANGAWA Kenji

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    Grant amount：\17940000 （ Direct Cost: \13800000 、 Indirect Cost：\4140000 ）

    Ghrelin is an endogenous ligand for the growth-hormone secretagogues receptor(GHS-R). In addition to its role in the regulation of growth hormone(GH) release, the 28-amino acid peptide also stimulates food intake and induces adiposity. Since GHS-R is detected in the heart and blood vessels, the role of this peptide in the regulation of cardiovascular function has been suggested. Recently, we investigated the effect of daily peripheral ghrelin administration for 2 weeks in a rat model of myocardial infarction and found that ghrelin significantly attenuated cardiac dysfunction and remodeling induced by infarction. Interestingly, chronic administration of ghrelin dramatically suppressed the increase in heart rate and plasma noradrenaline concentration after infarction to the levels similar to sham-operated controls. The effects of ghrelin were accompanied by a decrease in the ratio of the low-to-high frequency spectra of heart rate variability. Moreover, we have also shown that one-shot subcutaneous administration of ghrelin in the very acute phase following infarction effectively rescues cardiac dysfunction/remodeling, prevents arrhythmias and significantly improves mortality. By the direct recoding of cardiac sympathetic nerve activity, it is demonstrated that early ghrelin administration suppresses cardiac sympathetic nerve activity excessively activated after infarction. Surprisingly, one-shot ghrelin administration in the acute phase of myocardial infarction improved cardiac dysfunction and sympathetic hyperactivity in the chronic phase. It is, therefore, suggested that ghrelin is potentially useful as a novel therapy for heart failure, arrhythmia and death in myocardial infarction, with its unique mechanism of action.

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  • Development of the new cardiovascular disease therapy making the most of unique characterization of physiologically active peptides.

    Grant number：19790548  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    TOKUDOME Takeshi

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    Grant amount：\3690000 （ Direct Cost: \3300000 、 Indirect Cost：\390000 ）

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  • Molecular Elucidation for Endogenous Cardioprotective Mechanism -Towards Discovery for New Cardiac Treatment

    Grant number：19590845  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KISHIMOTO Ichiro, TOKUDOME Takeshi

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • Antiatherosclerotic therapy using cell differentiation-promoting effect of biologically active peptides

    Grant number：18590829  2006 - 2007

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    HORIO Takeshi, TOKUDOME Takeshi, KISHIMOTO Ichiro, KANGAWA Kenji

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    Grant amount：\3890000 （ Direct Cost: \3500000 、 Indirect Cost：\390000 ）

    We first examined the expression of receptors for natriuretic peptides(ANP, BNP, CNP) in wire-injured femoral arteries in mice. Significant expressions of both GC-A(receptor for ANP and BNP) and GC-B(receptor for CNP) were found in neointima after 3 weeks of wire injury, and the expression level of GC-A was higher than that of GC-B. When the extent of wire injury-induced neointima formation was compared between wild-type and GC-A knockout mice, the area of neointima was greater in GC-A knockout mice. This result suggested the possibility that endogenous ANP and BNP released from the heart inhibited atherosclerotic change of femoral artery after wire injury. To further examine the role of endogenous ANP and BNP in neovascularization observed in atherosclerotic lesions, lower limb-ischemic model was made in both wild-type and GC-A knockout mice, and the recovery of blood flow was evaluated. The blood flow was restored to about 70% after 3 weeks in wild-type mice. On the other hand, interestingly, the recovery rate of blood flow in GC-A knockout mice was about 20%, and approximately half of them had necrotized lower limbs. The finding suggested that endogenous ANP and BNP might play an important role in the angiogenesis in ischemic lesions. From these results, an in vitro study was designed to investigate whether ANP and BNP, stimulate cyclic GMP(cGMP) accumulation in vascular endothelial progenitor cells derived from human blood mononuclear cells. As a result, intracellular cGMP levels were remarkably elevated after stimulation with ANP and BNP, suggesting that these peptides have a direct effect on endothelial progenitor cells. Our findings indicate that endogenous ANP and BNP are involved not only in the inhibition of the formation of atherosclerotic lesions, but also in the promotion of neovascularization in those lesions. Thus, the present study provided a great progress forclinical application of antiatherosclerotic therapy using cell differentiation-promoting effect of ANP and BNP. We will forward further investigations about antiatherosclerotic effects and therapeutic application of CNP, adrenomedulin, and ghrelin.

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