KUNO Atsushi

写真a

Affiliation

School of Medicine, Department of Pharmacology

Job title

Professor
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Degree 【 display / non-display 】

  • 札幌医科大学   医学博士

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Professional Memberships 【 display / non-display 】

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    THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

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    The Japanese Circulation Society

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    THE JAPANESE SOCIETY OF INTERNAL MEDICINE

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    国際心臓研究学会

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    米国心臓協会

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Research Areas 【 display / non-display 】

  • Life sciences   Pharmacology  

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Affiliation 【 display / non-display 】

  • Sapporo Medical University   医学部薬理学講座   教授  

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Papers 【 display / non-display 】

  • Transcriptional dysregulation of autophagy in the muscle of a mouse model of Duchenne muscular dystrophy.

    Ryuta Nakashima, Ryusuke Hosoda, Yuki Tatekoshi, Naotoshi Iwahara, Yukika Saga, Atsushi Kuno

    Scientific reports   14 ( 1 ) 1365 - 1365  2024.01  [Refereed]  [International journal]

    Authorship：   Corresponding author

    　View Summary

    It has been reported that autophagic activity is disturbed in the skeletal muscles of dystrophin-deficient mdx mice and patients with Duchenne muscular dystrophy (DMD). Transcriptional regulations of autophagy by FoxO transcription factors (FoxOs) and transcription factor EB (TFEB) play critical roles in adaptation to cellular stress conditions. Here, we investigated whether autophagic activity is dysregulated at the transcription level in dystrophin-deficient muscles. Expression levels of autophagy-related genes were globally decreased in tibialis anterior and soleus muscles of mdx mice compared with those of wild-type mice. DNA microarray data from the NCBI database also showed that genes related to autophagy were globally downregulated in muscles from patients with DMD. These downregulated genes are known as targets of FoxOs and TFEB. Immunostaining showed that nuclear localization of FoxO1 and FoxO3a was decreased in mdx mice. Western blot analyses demonstrated increases in phosphorylation levels of FoxO1 and FoxO3a in mdx mice. Nuclear localization of TFEB was also reduced in mdx mice, which was associated with elevated phosphorylation levels of TFEB. Collectively, the results suggest that autophagy is disturbed in dystrophin-deficient muscles via transcriptional downregulation due to phosphorylation-mediated suppression of FoxOs and TFEB.

    DOI PubMed

  • Circulating level of β-aminoisobutyric acid (BAIBA), a novel myokine-like molecule, is inversely associated with fat mass in patients with heart failure

    Satoshi Katano, Toshiyuki Yano, Hidemichi Kouzu, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Katsuhiko Ohori, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Masaki Katayose, Tatsuya Sato, Atsushi Kuno, Masato Furuhashi

    Heart and Vessels ( Springer Science and Business Media LLC )   2023.09  [Refereed]

    DOI

  • Resveratrol, a SIRT1 activator, attenuates aging-associated alterations in skeletal muscle and heart in mice.

    Ryusuke Hosoda, Ryuta Nakashima, Masaki Yano, Naotoshi Iwahara, Seidai Asakura, Iyori Nojima, Yukika Saga, Risa Kunimoto, Yoshiyuki Horio, Atsushi Kuno

    Journal of Pharmacological Sciences ( Elsevier BV )   2023.04  [Refereed]

    Authorship：   Corresponding author

    DOI

  • Adenosine monophosphate deaminase in the endoplasmic reticulum-mitochondria interface promotes mitochondrial Ca2+ overload in type 2 diabetes rat hearts.

    Arata Osanami, Tatsuya Sato, Yuki Toda, Masaki Shimizu, Atsushi Kuno, Hidemichi Kouzu, Toshiyuki Yano, Wataru Ohwada, Toshifumi Ogawa, Tetsuji Miura, Masaya Tanno

    Journal of diabetes investigation    2023.02  [Refereed]  [Domestic journal]

    　View Summary

    AIMS/INTRODUCTION: We previously showed that upregulation of myocardial adenosine monophosphate deaminase (AMPD) is associated with pressure overload-induced diastolic dysfunction in type 2 diabetes hearts. Here, we examined involvement of AMPD localized in the endoplasmic reticulum-mitochondria interface in mitochondrial Ca2+ overload and its pathological significance. MATERIALS AND METHODS: We used type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats (OLETF) and non-diabetes Long-Evans Tokushima Otsuka Fatty rats (LETO) as well as AMPD3-overexpressing H9c2 cells and human embryonic kidney 293 cells. RESULTS: OLETF, but not LETO, showed diastolic dysfunction under the condition of phenylephrine-induced pressure overload. The levels of 90-kDa AMPD3 in outer mitochondrial membranes/endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane (MAM) fractions were significantly higher in OLETF than in LETO. The area of the MAM quantified by electron microscopic analysis was 57% larger, mitochondrial Ca2+ level under the condition of pressure overload was 47% higher and Ca2+ retention capacity in MAM-containing crude mitochondria isolated before the pressure overloading was 21% lower in OLETF than in LETO (all P-values <0.05). Transfection of FLAG-AMPD3 in cells resulted in significant enlargement of the MAM area, and impairment in pyruvate/malate-driven adenosine triphosphate-stimulated and uncoupler-stimulated mitochondrial respiration compared with those in control cells. CONCLUSIONS: The findings suggest that 90-kDa AMPD3 localized in the endoplasmic reticulum-mitochondria interface promotes formation of the MAM, inducing mitochondrial Ca2+ overload and dysfunction in type 2 diabetes hearts.

    DOI PubMed

  • Nuclear translocation of MLKL enhances necroptosis by a RIP1/RIP3-independent mechanism in H9c2 cardiomyoblasts.

    Shoya Ino, Toshiyuki Yano, Atsushi Kuno, Masaya Tanno, Hidemichi Kouzu, Tatsuya Sato, Tomohisa Yamashita, Wataru Ohwada, Arata Osanami, Toshifumi Ogawa, Yuki Toda, Masaki Shimizu, Tetsuji Miura

    Journal of pharmacological sciences   151 ( 2 ) 134 - 143  2023.02  [Refereed]  [Domestic journal]

    　View Summary

    Accumulating evidence suggests that necroptosis of cardiomyocytes contributes to cardiovascular diseases. Lethal disruption of the plasma membrane in necroptosis is induced by oligomers of mixed lineage kinase domain-like (MLKL) that is translocated to the membrane from the cytosol. However, the role played by cytoplasmic-nuclear shuttling of MLKL is unclear. Here, we tested the hypothesis that translocation of MLKL to the nucleus promotes the necroptosis of cardiomyocytes. Activation of the canonical necroptotic signaling pathway by a combination of TNF-α and zVAD (TNF/zVAD) increased nuclear MLKL levels in a RIP1-activity-dependent manner in H9c2 cells, a rat cardiomyoblast cell line. By use of site-directed mutagenesis, we found a nuclear export signal sequence in MLKL and prepared its mutant (MLKL-L280/283/284A), though a search for a nuclear import signal was unsuccessful. MLKL-L280/283/284A localized to both the cytosol and the nucleus. Expression of MLKL-L280/283/284A induced necroptotic cell death, which was attenuated by GppNHp, an inhibitor of Ran-mediated nuclear import, but not by inhibition of RIP1 activity or knockdown of RIP3 expression. GppNHp partly suppressed H9c2 cell death induced by TNF/zVAD treatment. These results suggest that MLKL that is translocated to the nucleus via RIP1-mediated necroptotic signaling enhances the necroptosis of cardiomyocytes through a RIP1-/RIP3-independent mechanism.

    DOI PubMed

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Misc 【 display / non-display 】

  • SIRT1は脱アセチル化を介してヒストンH2AXのリン酸化を媒介しドキソルビシン誘発性心毒性を弱める(SIRT1 Mediates Histone H2AX Phosphorylation via Its Deacetylation and Counteracts Doxorubicin-induced Cardiotoxicity)

    久野 篤史, 細田 隆介

    日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  86回   PJ21 - 1  2022.03

  • 健康食品とサーチュイン遺伝子（長寿遺伝子）：総論

    久野 篤史

    日本食品安全協会会誌   17 ( 1 ) 3 - 9  2022.01

    Authorship：   Lead author  , Corresponding author

  • 【目標を見据えた高齢者糖尿病管理〜実態の理解から薬物療法まで〜】糖尿病・血糖降下薬と長寿遺伝子サーチュイン

    久野 篤史

    月刊糖尿病 ( (株)医学出版 )  13 ( 11 ) 86 - 93  2021.11

  • レスベラトロールによる筋ジストロフィーの治療

    福村 忍, 川村 健太郎, 山本 晃代, 堀尾 嘉幸, 久野 篤史, 堤 裕幸

    BIO Clinica ( (株)北隆館 )  36 ( 9 ) 910 - 914  2021.08

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    レスベラトロールはDuchenne型筋ジストロフィーモデルのmdxマウスに対して、組織の酸化ストレス低下、筋蛋白質量の増加、線維化の抑制、骨格筋と心筋機能の低下抑制とクレアチンキナーゼ低下作用を示した。筋ジストロフィーを対象とした臨床研究ではレスベラトロールによる有意な運動機能の向上と筋力増加を確認した。レスベラトロールは筋ジストロフィー治療薬として有用と考えられる。(著者抄録)

  • 【食・栄養から健康を拓く生化学】レスベラトロールの生体作用とその標的SIRT1

    久野 篤史, 堀尾 嘉幸

    生化学 ( (公社)日本生化学会 )  93 ( 1 ) 100 - 108  2021.02

    　View Summary

    レスベラトロールはブドウの果皮や赤ワインなどに豊富に含まれるポリフェノールである.NAD+依存性タンパク質脱アセチル化酵素SIRT1を活性化させる植物由来物質としてレスベラトロールが同定されて以来,レスベラトロールは種々の疾患への治療薬となる可能性があるとして注目を集めてきた.我々はレスベラトロールの持つ細胞保護効果に着目し,心疾患および骨格筋疾患モデルにおける有効性と,その機序におけるSIRT1の役割を検討してきた.本稿では,レスベラトロールの生体における作用をその主な標的分子であるSIRT1との関連から概説し,我々のレスベラトロールの心疾患・骨格筋疾患に対する治療効果に関する研究成果を紹介する.レスベラトロールはさまざまな疾患の予防や治療において期待のできる植物由来物質である.(著者抄録)

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Industrial Property Rights 【 display / non-display 】

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Research Projects 【 display / non-display 】

  • 心不全におけるオートファジー障害の機序解明と治療への応用

    Grant-in-Aid for Scientific Research (C)

    Project Year :

    2020.04
    -
    2023.03
     

    久野 篤史, 藤谷 直樹, 野島 伊世里, 堀尾 嘉幸, 矢野 俊之

  • Novel role of SIRT1 in regulation of autophagy and its role in heart failure

    Grant-in-Aid for Scientific Research (C)

    Project Year :

    2017.04
    -
    2020.03
     

    Kuno Atsushi

    　View Summary

    We investigated how SIRT1 regulates autophagy/mitophagy and its role in heart diseases. We found that administration of the SIRT1 activator to mdx mice, a model of muscular dystrophy, restored mitophagy in the heart and led to the improvement in cardiac function. In cardiomyocytes, knockdown of SIRT1 blocked CCCP-induced mitophagy and interrupted fusion of autophagosomes and lysosomes. These results suggest that SIRT1 is involved in autophagosome-lysosome fusion to promotes autophagy/mitophagy and protects the heart via autophagy/mitophagy activation.

  • 糖尿病による急性腎障害の増悪におけるオートファジー・ネクロプトーシスの役割

    基盤研究(C)

    Project Year :

    2023.04
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    2026.03
     

    久野 篤史

  • 糖尿病による急性腎障害増悪におけるオートファジー・ネ クロプトーシス連関の役割解明

    Project Year :

    2022.12
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    2023.11
     

    久野 篤史

    Authorship： Principal investigator

  • スチルベノイド含有植物素材による筋萎縮予防の実用化に向けた研究

    Project Year :

    2022.08
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    2023.03
     

    Authorship： Principal investigator

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Presentations 【 display / non-display 】

  • Restoration of impaired autophagosome clearance underlies amelioration of cardiomyopathy afforded by SIRT1 activation in dystrophin-deficient mice.

    Atsushi Kuno

    ISHR2017 

    Presentation date： 2017.12

  • SIRT1 Protects against Doxorubicin Cardiotoxicity In Vivo.

    Atsushi Kuno

    第80回 日本循環器学会 

    Presentation date： 2016.03

  • SIRT1の活性化はマイトファジーにより障害ミトコンドリアを除去して筋ジストロフィー心筋障害を軽減する

    久野 篤史

    第41回日本分子生物学会年会 

    Presentation date： 2018.11

  • The SIRT1 activator resveratrol ameliorates dystrophic cardiomyopathy by promoting mitophagy.

    Atsushi Kuno

    European Society of Cardiology Congress 2018 

    Presentation date： 2018.08

  • Role of impaired autophagy caused by aberrant activation of mTORC1 in dystrophic cardiomyopathy.

    Atsushi Kuno

    Keystone Symposia Conference: Aging and Mechanisms of Aging-Related Disease 

    Presentation date： 2017.05

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