2025/06/01 更新

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写真a

イトウ トモヤ
伊藤 智哉
ITO TOMOYA
所属
薬学研究院 臨床薬学部門 助教
薬学部 臨床薬学科(併任)
薬学府 臨床薬学専攻(併任)
職名
助教
連絡先
メールアドレス
電話番号
0926426585

研究分野

  • ライフサイエンス / 分子生物学

学位

  • 博士(理学)

経歴

  • 九州大学 大学院薬学研究院 助教 

    2024年4月 - 現在

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  • 2014.10 - 2014.12 東京工業大学 バイオ研究基盤支援総合センター 教育支援員 2015.01 - 2015.03 京都大学大学院工学研究科 合成・生物化学専攻 教務補佐員 2015.04 - 2016.09 自然科学研究機構生理学研究所 生体情報研究系 心循環シグナル研究部門 博士研究員(NIPS リサーチフェロー) 2016.10 - 2024.03 英国ロンドン大学クイーン・メアリー校ウィリアム・ハーベイ研究所 博士研究員   

論文

  • TRP channels in cardiac mechano-redox coupling and diseases 国際誌

    Mi X., Wu D., Ito T., Kato Y., Nishimura A., Nishida M.

    Journal of Cardiology   2025年2月   ISSN:09145087

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Cardiology  

    Reactive oxygen species (ROS) produced by mechanically stretching cardiomyocytes is a crucial mediator to increase contractile force in accordance with the Frank-Starling law. However, excessive ROS production leads to oxidative stress, contributing to myocardial atrophic remodeling and cellular damage. NADPH oxidase, the primary enzyme responsible for ROS production localized on the plasma membrane and organelle membranes, plays a key role in membrane-oriented ROS signaling. Two isoforms of NADPH oxidase, Nox2 (constitutive) and Nox4 (inducible), are predominantly expressed in cardiomyocytes, each playing unique roles in different contexts. Recent studies have revealed that Nox proteins form protein signaling complexes with transient receptor potential (TRP) channel proteins, amplifying ROS signaling in hearts. This review presents the putative mechanism of protein-protein interaction between TRP and Nox and their pathophysiological significance in hearts and discusses therapeutic strategies targeting TRP-Nox protein interactions for the treatment of heart failure.

    DOI: 10.1016/j.jjcc.2025.02.016

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  • Ligand-Independent Spontaneous Activation of Purinergic P2Y<inf>6</inf> Receptor Under Cell Culture Soft Substrate

    Nishimura A., Nishiyama K., Ito T., Mi X., Kato Y., Inoue A., Aoki J., Nishida M.

    Cells   14 ( 3 )   2025年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cells  

    G protein-coupled receptors (GPCRs) exist in the conformational equilibrium between inactive state and active state, where the proportion of active state in the absence of a ligand determines the basal activity of GPCRs. Although many GPCRs have different basal activity, it is still unclear whether physiological stresses such as substrate stiffness affect the basal activity of GPCRs. In this study, we identified that purinergic P2Y6 receptor (P2Y6R) induced spontaneous Ca2+ oscillation without a nucleotide ligand when cells were cultured in a silicon chamber. This P2Y6R-dependent Ca2+ oscillation was absent in cells cultured in glass dishes. Coating substrates, including collagen, laminin, and fibronectin, did not affect the P2Y6R spontaneous activity. Mutation of the extracellular Arg-Gly-Asp (RGD) motif of P2Y6R inhibited spontaneous activity. Additionally, extracellular Ca2+ was required for P2Y6R-dependent spontaneous Ca2+ oscillation. The GPCR screening assay identified cells expressing 10 GPCRs, including purinergic P2Y1R, P2Y2R, and P2Y6R, that exhibited spontaneous Ca2+ oscillation under cell culture soft substrate. Our results suggest that stiffness of the cell adhesion surface modulates spontaneous activities of several GPCRs, including P2Y6R, through a ligand-independent mechanism.

    DOI: 10.3390/cells14030216

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  • TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells

    Su C., Mi X., Ito T., Kato Y., Nishimura A., Nagata R., Mori Y., Nishida M.

    Biomolecules   15 ( 2 )   2025年2月

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    記述言語:英語   出版者・発行元:Biomolecules  

    Vascular smooth muscle cells (VSMCs) can dynamically change their phenotype between contractile and synthetic forms in response to environmental stress, which is pivotal in maintaining vascular homeostasis and mediating pathological remodeling of blood vessels. We previously reported that suppression of canonical transient receptor potential 6 (TRPC6) channel-mediated cation entry sustains VSMCs contractile phenotype and promotes the blood flow recovery after hindlimb ischemia in mice. We also reported that Zn2+, a metal biomolecule mobilized by TRPC6 channel activation, exerts potential beneficial effects on cardiac contractility and remodeling. Therefore, we hypothesized that TRPC6-mediated Zn2+ influx participates in phenotype switching of VSMCs and vascular remodeling. We established rat aortic smooth muscle cells (RAoSMCs) stably expressing wild type (WT) and Zn2+ only impermeable TRPC6 (KYD) mutant. Although the resting phenotypes were similar in both RAoSMCs, pharmacological TRPC6 activation by PPZ2 prevented the transforming growth factor (TGF) β-induced reduction in the intracellular Zn2+ amount and contractile differentiation in RAoSMCs (WT), but failed to prevent them in RAoSMCs (KYD). There were no significant differences in TRPC6-dependent cation currents among all RAoSMCs pretreated with or without TGFβ and/or PPZ2, suggesting that TRPC6 channels are functionally expressed in RAoSMCs regardless of their phenotype. Treatment of mice with PPZ2 attenuated the progression of vascular remodeling caused by chronic angiotensin II infusion. These results suggest that Zn2+ influx through TRPC6 channels negatively regulates the TGFβ-induced contractile differentiation of VSMCs and the progression of vascular remodeling in rodents.

    DOI: 10.3390/biom15020267

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  • Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes 査読

    Kondo, M; Nakamura, Y; Kato, Y; Nishimura, A; Fukata, M; Moriyama, S; Ito, T; Umezawa, K; Urano, Y; Akaike, T; Akashi, K; Kanda, Y; Nishida, M

    JOURNAL OF PHARMACOLOGICAL SCIENCES   156 ( 2 )   69 - 76   2024年10月   ISSN:1347-8613 eISSN:1347-8648

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pharmacological Sciences  

    Despite the widespread recognition of the global concern regarding the onset of cardiovascular diseases in a significant number of patients following cancer treatment, definitive strategies for prevention and treatment remain elusive. In this study, we established systems to evaluate the influence of anti-cancer drugs on the quality control of mitochondria, pivotal for energy metabolism, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treatment in lung cancer, reportedly increases the risk of cardiovascular disease. However, its underlying mechanism is largely unknown. Here, we found that the treatment of hiPSC-CMs with osimertinib and doxorubicin, but not trastuzumab and cisplatin, revealed a concentration-dependent impairment of respiratory function accompanied by mitochondrial fission. We previously reported the significant role of sulfur metabolism in maintaining mitochondrial quality in the heart. Co-treatment with various inorganic sulfur donors (Na2S, Na2S2, Na2S3) alongside anti-cancer drugs demonstrated that Na2S attenuated the cardiotoxicity of osimertinib but not doxorubicin. Osimertinib decreased intracellular reduced sulfur levels, while Na2S treatment suppressed the sulfur leakage, suggesting its potential in mitigating osimertinib-induced cardiotoxicity. These results imply the prospect of inorganic sulfides, such as Na2S, as a seed for precision pharmacotherapy to alleviate osimertinib's cardiotoxic effects.

    DOI: 10.1016/j.jphs.2024.07.007

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  • 無機硫化物はヒトiPS細胞由来心筋細胞におけるオシメルチニブ誘発性ミトコンドリア機能障害を防止する(Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes)

    Kondo Moe, Nakamura Yuya, Kato Yuri, Nishimura Akiyuki, Fukata Mitsuhiro, Moriyama Shohei, Ito Tomoya, Umezawa Keitaro, Urano Yasuteru, Akaike Takaaki, Akashi Koichi, Kanda Yasunari, Nishida Motohiro

    Journal of Pharmacological Sciences   156 ( 2 )   69 - 76   2024年10月   ISSN:1347-8613

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    記述言語:英語   出版者・発行元:(公社)日本薬理学会  

    ヒト人工多能性幹細胞由来心筋細胞(hiPSC-CM)を用いて、ミトコンドリアに対する抗癌剤の影響を評価するためのシステムを作成した。hiPSC-CMをオシメルチニブ(Ost)とドキソルビシンで処理した結果、ミトコンドリア分裂を伴う呼吸機能障害が認められた。以前の報告を元に無機イオウドナー(Na2S、Na2S2、Na2S3)を抗癌剤と一緒に投与した。その結果、Na2SはOstの心毒性を弱めたが、ドキソルビシンの毒性は弱めなかった。Ostは細胞内の硫黄濃度を低下させ、Na2Sは硫黄の流出を抑制したことから、その作用がOstの心毒性を和らげることが示唆された。以上より、無機硫化物がOstの心毒性を緩和する薬物療法のシーズとして期待しうると考えられた。

  • Diabetic Mice Spleen Vulnerability Contributes to Decreased Persistence of Antibody Production after SARS-CoV-2 Vaccine 国際誌

    Atef, Y; Ito, T; Masuda, A; Kato, Y; Nishimura, A; Kanda, Y; Kunisawa, J; Kusakabe, T; Nishida, M

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   25 ( 19 )   2024年10月   ISSN:1661-6596 eISSN:1422-0067

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    During the COVID-19 pandemic, diabetic and obese patients experienced higher rates of hospital admissions, severe illness, and mortality. However, vaccinations failed to provide those vulnerable populations the same level of protection against COVID-19 severity as those without diabetic and obese phenotypes. Our study aimed to investigate how diabetes mellitus (DM) impacts the immune response following vaccination including the artificially designed trimeric SARS-CoV-2 spike (S)-protein. By using two diabetic mouse models, ob/ob mice (obese, hyperglycemic, and insulin-resistant) and STZ-treated mice (insulin-deficient and hyperglycemic), we observed a significant reduction in S-protein-specific IgG antibody titer post-vaccination in both diabetic models compared to wild-type (WT) mice. Both diabetic mouse models exhibited significant abnormalities in spleen tissue, including marked reductions in splenic weight and the size of the white pulp regions. Furthermore, the splenic T-cell and B-cell zones were notably diminished, suggesting an underlying immune dysfunction that could contribute to impaired antibody production. Notably, vaccination with the S-protein, when paired with an optimal adjuvant, did not exacerbate diabetic cardiomyopathy, blood glucose levels, or liver function, providing reassurance about the vaccine′s safety. These findings offer valuable insights into potential mechanisms responsible for the decreased persistence of antibody production in diabetic patients.

    DOI: 10.3390/ijms251910379

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  • Supersulfide catabolism participates in maladaptive remodeling of cardiac cells 査読

    Zhou, LCZ; Nishimura, A; Umezawa, K; Kato, Y; Mi, XY; Ito, T; Urano, Y; Akaike, T; Nishida, M

    JOURNAL OF PHARMACOLOGICAL SCIENCES   155 ( 4 )   121 - 130   2024年8月   ISSN:1347-8613 eISSN:1347-8648

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pharmacological Sciences  

    The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart failure, as well as interstitial fibrosis. Conversely, myocardial hypertrophy resulting from hemodynamic loading is perceived as compensatory stress adaptation. We previously reported the abundant presence of highly redox-active polysulfide molecules, termed supersulfide, with two or more sulfur atoms catenated in normal hearts, and the supersulfide catabolism in pathologic hearts after myocardial infarction correlated with worsened prognosis of heart failure. However, the impact of supersulfide on myocardial remodeling remains unclear. Here, we investigated the involvement of supersulfide metabolism in cardiomyocyte remodeling, using a model of adenosine 5′-triphosphate (ATP) receptor-stimulated atrophy and endothelin-1 receptor-stimulated hypertrophy in neonatal rat cardiomyocytes. Results revealed contrasting changes in intracellular supersulfide and its catabolite, hydrogen sulfide (H2S), between cardiomyocyte atrophy and hypertrophy. Stimulation of cardiomyocytes with ATP decreased supersulfide activity, while H2S accumulation itself did not affect cardiomyocyte atrophy. This supersulfide catabolism was also involved in myofibroblast formation of neonatal rat cardiac fibroblasts. Thus, unraveling supersulfide metabolism during myocardial remodeling may lead to the development of novel therapeutic strategies to improve heart failure.

    DOI: 10.1016/j.jphs.2024.05.002

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  • 超硫黄分子異化は心臓細胞の不適応リモデリングに関与する(Supersulfide catabolism participates in maladaptive remodeling of cardiac cells)

    Zhou Liuchenzi, Nishimura Akiyuki, Umezawa Keitaro, Kato Yuri, Mi Xinya, Ito Tomoya, Urano Yasuteru, Akaike Takaaki, Nishida Motohiro

    Journal of Pharmacological Sciences   155 ( 4 )   121 - 130   2024年8月   ISSN:1347-8613

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    記述言語:英語   出版者・発行元:(公社)日本薬理学会  

    ラット新生仔心筋細胞におけるATP受容体刺激萎縮とエンドセリン-1刺激肥大のモデルを用い、リモデリングにおける超硫黄分子の関与を解析した。心筋細胞の萎縮と肥大にて、細胞内超硫黄分子とその代謝物の硫化水素(H2S)の対照的な変化が観察された。心筋細胞のATP刺激は超硫黄分子の活性を低下させ、H2S蓄積は心筋萎縮に影響を与えなかった。この超硫黄分子の異化作用は新生仔ラットの心臓における線維芽細胞の筋線維芽細胞の形成にも関与していた。

  • Sulfur metabolism as a new therapeutic target of heart failure 査読

    Nishimura, A; Tang, XK; Zhou, LCZ; Ito, T; Kato, Y; Nishida, M

    JOURNAL OF PHARMACOLOGICAL SCIENCES   155 ( 3 )   75 - 83   2024年7月   ISSN:1347-8613 eISSN:1347-8648

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pharmacological Sciences  

    Sulfur-based redox signaling has long attracted attention as critical mechanisms underlying the development of cardiac diseases and resultant heart failure. Especially, post-translational modifications of cysteine (Cys) thiols in proteins mediate oxidative stress-dependent cardiac remodeling including myocardial hypertrophy, senescence, and interstitial fibrosis. However, we recently revealed the existence of Cys persulfides and Cys polysulfides in cells and tissues, which show higher redox activities than Cys and substantially contribute to redox signaling and energy metabolism. We have established simple evaluation methods that can detect polysulfides in proteins and inorganic polysulfides in cells and revealed that polysulfides abundantly expressed in normal hearts are dramatically catabolized by exposure to ischemic/hypoxic and environmental electrophilic stress, which causes vulnerability of the heart to mechanical load. Accumulation of hydrogen sulfide, a nucleophilic catabolite of persulfides/polysulfides, may lead to reductive stress in ischemic hearts, and perturbation of polysulfide catabolism can improve chronic heart failure after myocardial infarction in mice. This review focuses on the (patho)physiological role of sulfur metabolism in hearts, and proposes that sulfur catabolism during ischemic/hypoxic stress has great potential as a new therapeutic strategy for the treatment of ischemic heart failure.

    DOI: 10.1016/j.jphs.2024.04.005

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  • Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contact 査読

    Ariyoshi, K; Nishiyama, K; Kato, Y; Mi, XY; Ito, T; Azuma, YT; Nishimura, A; Nishida, M

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   25 ( 10 )   2024年5月   ISSN:1661-6596 eISSN:1422-0067

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein–protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1–filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1–filamin interaction become a new strategy for the prevention or treatment of fatty liver disease.

    DOI: 10.3390/ijms25105446

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  • Supersulfide prevents cigarette smoke extract-induced mitochondria hyperfission and cardiomyocyte early senescence by inhibiting Drp1-filamin complex formation 査読

    Nishimura, A; Zhou, LCZ; Kato, Y; Mi, XY; Ito, T; Ibuki, Y; Kanda, Y; Nishida, M

    JOURNAL OF PHARMACOLOGICAL SCIENCES   154 ( 2 )   127 - 135   2024年2月   ISSN:1347-8613 eISSN:1347-8648

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pharmacological Sciences  

    Smoking is one of the most serious risk factors for cardiovascular diseases. Although cigarette mainstream and sidestream smoke are significant contributors to increased cardiovascular mortality and morbidity, the underlying mechanism is still unclear. Here, we report that exposure of rat neonatal cardiomyocytes to cigarette smoke extract (CSE) induces mitochondrial hyperfission-mediated myocardial senescence. CSE leads to mitochondrial fission and reactive oxygen species (ROS) production through the complex formation between mitochondrial fission factor Drp1 and actin-binding protein, filamin A. Pharmacological perturbation of interaction between Drp1 and filamin A by cilnidipine and gene knockdown of Drp1 or filamin A inhibited CSE-induced mitochondrial hyperfission and ROS production as well as myocardial senescence. We previously reported that Drp1 activity is controlled by supersulfide-induced Cys644 polysulfidation. The redox-sensitive Cys644 was critical for CSE-mediated interaction with filamin A. The administration of supersulfide donor, Na2S3 also improved mitochondrial hyperfission-mediated myocardial senescence induced by CSE. Our results suggest the important role of Drp1-filamin A complex formation on cigarette smoke-mediated cardiac risk and the contribution of supersulfide to mitochondrial fission-associated myocardial senescence.

    DOI: 10.1016/j.jphs.2023.12.008

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  • 超硫黄分子はDrp1-フィラミン複合体形成を阻害してタバコ煙抽出物によるミトコンドリアの過剰分裂と心筋細胞早期老化を防止する(Supersulfide prevents cigarette smoke extract-induced mitochondria hyperfission and cardiomyocyte early senescence by inhibiting Drp1-filamin complex formation)

    Nishimura Akiyuki, Zhou Liuchenzi, Kato Yuri, Mi Xinya, Ito Tomoya, Ibuki Yuko, Kanda Yasunari, Nishida Motohiro

    Journal of Pharmacological Sciences   154 ( 2 )   127 - 135   2024年2月   ISSN:1347-8613

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    記述言語:英語   出版者・発行元:(公社)日本薬理学会  

    ラット新生仔の心筋細胞にタバコ煙抽出物(CSE)を曝露すると、ミトコンドリア(MT)過剰分裂を介して心筋細胞老化が誘発された。CSEはMT分裂因子Drp1とアクチン結合蛋白質であるフィラミンA(FIL-A)との複合体形成を介して、MT分裂と活性酸素種(ROS)産生を引き起こした。シルニジピンやDrp1またはFIL-Aの遺伝子ノックダウンによりDrp1とFIL-Aの相互作用が変化し、CSE誘発性MT過剰分裂とROS産生、および心筋細胞老化を阻害した。Drp1活性の中心である酸化還元感受性をもったCys644について、CSEを介したFIL-Aとの相互作用において重要な役割を果たしていた。超硫黄分子(SS)供与体Na2S3の投与により、CSE誘発性MT過剰分裂を介して心筋細胞老化を改善した。以上より、Drp1-FIL-A複合体形成がタバコ煙介在性心リスクにおいて重要な役割を果たしており、MT分裂関連心筋細胞老化に対するSSの寄与が考えられた。

  • Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data 査読

    Laura Fields, Tomoya Ito, Kazuya Kobayashi, Yuki Ichihara, Mihai-Nicolae Podaru, Mohsin Hussain, Kizuku Yamashita, Vanessa Machado, Fiona Lewis-McDougall, Ken Suzuki

    Molecular Therapy   29 ( 8 )   2554 - 2570   2021年8月

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    DOI: 10.1016/j.ymthe.2021.04.018

  • Cell barrier function of resident peritoneal macrophages in post-operative adhesions 査読

    Tomoya Ito, Yusuke Shintani, Laura Fields, Manabu Shiraishi, Mihai‑Nicolae Podaru, Satoshi Kainuma, Kizuku Yamashita, Kazuya Kobayashi, Mauro Perretti, Fiona Lewis-McDougall, Ken Suzuki

    Nature Communications   2021年4月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41467-021-22536-y

  • Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice 査読

    Kakeru Shimoda, Akiyuki Nishimura, Caroline Sunggip, Tomoya Ito, Kazuhiro Nishiyama, Yuri Kato, Tomohiro Tanaka, Hidetoshi Tozaki-Saitoh, Makoto Tsuda, Motohiro Nishida

    Scientific Reports   10 ( 1 )   2020年8月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Abstract

    Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.

    DOI: 10.1038/s41598-020-70956-5

  • Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy 査読

    Mihai-Nicolae Podaru, Laura Fields, Satoshi Kainuma, Yuki Ichihara, Mohsin Hussain, Tomoya Ito, Kazuya Kobayashi, Anthony Mathur, Fulvio D’Acquisto, Fiona Lewis-McDougall, Ken Suzuki

    Basic Research in Cardiology   114 ( 5 )   2019年8月

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    Abstract

    Reparative macrophages play an important role in cardiac repair post-myocardial infarction (MI). Bone marrow mononuclear cells (BM-MNCs) have been investigated as a donor for cell therapy but with limited clinical success. These cells, however, may be utilized as a source for reparative macrophages. This translational study aimed to establish a robust in vitro protocol to produce functional reparative macrophages from BM-MNCs and to establish pre-clinical evidence of the efficacy of reparative macrophage transplantation for the treatment of MI. Mouse BM-MNCs were treated with M-CSF plus IL-4, IL-10, TGF-β1 or combinations of these in vitro. The concomitant administration of M-CSF and IL-4 produced the highest rate and largest number of CD11b+F4/80+CD206+ reparative macrophages. Expression and secretion of tissue repair-related factors including IGF-1, TGF-β1, VEGF and IL1-ra were remarkably enhanced in reparative macrophages compared to BM-MNCs. These cells were transplanted in a mouse MI model, resulting in evident improvement in cardiac function recovery, compared to BM-MNC transplantation. Histological studies showed that reparative macrophage transplantation enhanced myocardial tissue repair including augmented microvascular formation, reduced cardiomyocyte hypertrophy and attenuated interstitial fibrosis. Moreover, survival of reparative macrophages in the heart post-transplantation was increased compared to BM-MNCs. Reparative macrophage transplantation also increased host-derived reparative macrophages in part through TGF-β secretion. In conclusion, concomitant M-CSF + IL-4 treatment effectively produced reparative macrophages from BM-MNCs in vitro. Transplantation of produced reparative macrophage achieved a superior therapeutic efficacy, compared to BM-MNC transplantation, through the enhanced quantity and quality of donor cell engraftment. Further development of this advanced cell-based therapy is warranted.

    DOI: 10.1007/s00395-019-0742-1

  • On-site fabrication of Bi-layered adhesive mesenchymal stromal cell-dressings for the treatment of heart failure 査読

    Kazuya Kobayashi, Yuki Ichihara, Nobuhiko Sato, Nobuyoshi Umeda, Laura Fields, Masafumi Fukumitsu, Yoshiyuki Tago, Tomoya Ito, Satoshi Kainuma, Mihai Podaru, Fiona Lewis-McDougall, Kenichi Yamahara, Rakesh Uppal, Ken Suzuki

    Biomaterials   209   41 - 53   2019年7月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.biomaterials.2019.04.014

  • Fibrin Glue-aided, Instant Epicardial Placement Enhances the Efficacy of Mesenchymal Stromal Cell-Based Therapy for Heart Failure 査読

    Kazuya Kobayashi, Yuki Ichihara, Nobuko Tano, Laura Fields, Nilaani Murugesu, Tomoya Ito, Chiho Ikebe, Fiona Lewis, Kenta Yashiro, Yasunori Shintani, Rakesh Uppal, Ken Suzuki

    Scientific Reports   8 ( 1 )   2018年6月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Abstract

    Transplantation of mesenchymal stromal cells (MSCs) is a promising new therapy for heart failure. However, the current cell delivery routes result in poor donor cell engraftment. We therefore explored the role of fibrin glue (FG)-aided, instant epicardial placement to enhance the efficacy of MSC-based therapy in a rat ischemic cardiomyopathy model. We identified a feasible and reproducible method to instantly produce a FG-MSC complex directly on the heart surface. This complex exhibited prompt, firm adhesion to the heart, markedly improving initial retention of donor MSCs compared to intramyocardial injection. In addition, maintenance of retained MSCs was enhanced using this method, together contributing the increased donor cell presence. Such increased donor cell quantity using the FG-aided technique led to further improved cardiac function in association with augmented histological myocardial repair, which correlated with upregulation of tissue repair-related genes. We identified that the epicardial layer was eliminated shortly after FG-aided epicardial placement of MSCs, facilitating permeation of the donor MSC’s secretome into the myocardium enabling myocardial repair. These data indicate that FG-aided, on-site, instant epicardial placement enhances MSC engraftment, promoting the efficacy of MSC-based therapy for heart failure. Further development of this accessible, advanced MSC-therapy is justified.

    DOI: 10.1038/s41598-018-27881-5

  • TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy 査読

    Tsukasa Shimauchi, Takuro Numaga-Tomita, Tomoya Ito, Akiyuki Nishimura, Ryosuke Matsukane, Sayaka Oda, Sumio Hoka, Tomomi Ide, Norimichi Koitabashi, Koji Uchida, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida

    JCI Insight   2 ( 15 )   2017年8月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1172/jci.insight.93358

  • IL-4 as a Repurposed Biological Drug for Myocardial Infarction through Augmentation of Reparative Cardiac Macrophages: Proof-of-Concept Data in Mice 査読

    Yusuke Shintani, Tomoya Ito, Laura Fields, Manabu Shiraishi, Yuki Ichihara, Nobuhiko Sato, Mihai Podaru, Satoshi Kainuma, Hiroyuki Tanaka, Ken Suzuki

    Scientific Reports   7 ( 1 )   2017年7月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Abstract

    Recent research has shown that reparative (alternatively activated or M2) macrophages play a role in repair of damaged tissues, including the infarcted hearts. Administration of IL-4 is known to augment M2 macrophages. This translational study thus aimed to investigate whether IL-4 administration is useful for the treatment of myocardial infarction. Long-acting IL-4 complex (IL-4c; recombinant IL-4 mixed with anti-IL-4 monoclonal antibody as a stabilizer) was administered after coronary artery ligation in mice. It was observed that IL-4c administration increased accumulation of CD206+F4/80+ M2-like macrophages predominantly in the injured myocardium, compared to the control. Sorted cardiac M2-like macrophages highly expressed wide-ranging tissue repair-related genes. Indeed, IL-4c administration enhanced cardiac function in association with reduced infarct size and enhanced tissue repair (strengthened connective tissue formation, improved microvascular formation and attenuated cardiomyocyte hypertrophy). Experiments using Trib1−/− mice that had a depleted ability to develop M2 macrophages and other in-vitro studies supported that these IL-4-mediated effects were induced via M2-like macrophages. On the other hand, when administered at Day 28 post-MI, the effects of IL-4c were diminished, suggesting a time-frame for IL-4 treatment to be effective. These data represent proof-of-concept of efficacy of IL-4 treatment for acute myocardial infarction, encouraging its further development.

    DOI: 10.1038/s41598-017-07328-z

  • Genes that integrate multiple adipogenic signaling pathways in human mesenchymal stem cells 査読

    Tomoya Ito, So Tsuruta, Koki Tomita, Kunio Kikuchi, Takahide Yokoi, Yasunori Aizawa

    Biochemical and Biophysical Research Communications   409 ( 4 )   786 - 791   2011年6月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrc.2011.05.089

  • Transcripts of unknown function in multiple-signaling pathways involved in human stem cell differentiation 査読

    Kunio Kikuchi, Makiha Fukuda, Tomoya Ito, Mitsuko Inoue, Takahide Yokoi, Suenori Chiku, Toutai Mitsuyama, Kiyoshi Asai, Tetsuro Hirose, Yasunori Aizawa

    Nucleic Acids Research   37 ( 15 )   4987 - 5000   2009年6月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/nar/gkp426

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講演・口頭発表等

MISC

担当授業科目

  • 薬理・疾患治療

    2025年10月 - 2026年3月   後期

  • 生理学

    2025年6月 - 2025年8月   夏学期

  • 薬学基礎実習Ⅳ

    2025年6月 - 2025年8月   夏学期

  • 医療薬学演習Ⅰ

    2025年4月 - 2025年9月   前期

  • 医療薬学演習Ⅱ

    2025年4月 - 2025年9月   前期

  • 薬物治療学Ⅰ

    2025年4月 - 2025年6月   春学期

  • 医療薬学演習Ⅰ

    2024年4月 - 2024年9月   前期

  • 医療薬学演習Ⅱ

    2024年4月 - 2024年9月   前期

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