九州大学-研究者情報 [井手友美 (講師) 九州大学病院冠動脈疾患治療部]

心不全の病態と成因に関する研究（基礎研究および臨床研究）
心不全における酸化ストレスの役割
心血管病におけるミトコンドリア機能不全とミトコンドリアＤＮＡ
心不全における心臓リハビリテーションの役割と実践
自律神経と慢性心不全の調節機構とその治療的意義
迷走神経刺激と心血管病および認知機能に関する研究
キラルアミノ酸の心臓における役割に関する研究
キーワード：心不全、酸化ストレス、ミトコンドリア
2000.05.

主要著書

全てを見る→

1.	井手友美　砂川賢二, 心不全（下）　最新の基礎・臨床研究の進歩, 心不全治療概論　利尿薬, 2008.08.
2.	井手友美、　砂川賢二, 心不全（上）　最新の基礎・臨床研究の進歩, 日本臨床社, 65巻増刊号別冊, 2008.07.
3.	井手友美, 周術期患者への対応, 中山書店, 2007.12.
4.	Ide T, Tsutsui T, Sunagawa K, Oxygen radicals, mitochondria and heart failure, 167-176, 2005.12.

主要原著論文

全てを見る→

1.	Ko Abe, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Shun Furusawa, Yoshitomo Tsutsui, Ryo Miyake, Kosei Ishimaru, Masatsugu Watanabe, Shouji Matsushima, Tomoko Koumura, Ken-Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui, Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis., Science signaling, 10.1126/scisignal.abn8017, 15, 758, eabn8017, 2022.11, Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC..
2.	Masataka Ikeda, Tomomi Ide, Shouji Matsushima, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Tomonori Tadokoro, Masashi Sada, Ko Abe, Midori Sato, Akiko Hanada, Shinobu Arai, Kisho Ohtani, Atsushi Nonami, Shinichi Mizuno, Sachio Morimoto, Shinichiro Motohashi, Koichi Akashi, Masaru Taniguchi, Hiroyuki Tsutsui, Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model., Circulation. Heart failure, 10.1161/CIRCHEARTFAILURE.122.009366, 15, 12, e009366, 2022.10, BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated. METHODS: Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin TΔK210/ΔK210 with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. RESULTS: The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-β signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 (Angpt1) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-β-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated Angpt1 expression in cardiomyocytes via Stat1. CONCLUSIONS: Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM..
3.	Hiroko Deguchi Miyamoto, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Shun Furusawa, Ko Abe, Kosei Ishimaru, Nobuyuki Enzan, Masashi Sada, Taishi Yamamoto, Shouji Matsushima, Tomoko Koumura, Ken-Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui, Iron Overload via Heme Degradation in the Endoplasmic Reticulum Triggers Ferroptosis in Myocardial Ischemia-Reperfusion Injury., JACC. Basic to translational science, 10.1016/j.jacbts.2022.03.012, 7, 8, 800-819, 2022.08, Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron overload and excessive lipid peroxides, is reportedly involved in I/R injury. However, its significance and mechanistic basis remain unclear. Here, we show that glutathione peroxidase 4 (GPx4), a key endogenous suppressor of ferroptosis, determines the susceptibility to myocardial I/R injury. Importantly, ferroptosis is a major mode of cell death in I/R injury, distinct from mitochondrial permeability transition (MPT)-driven necrosis. This suggests that the use of therapeutics targeting both modes is an effective strategy to further reduce the infarct size and thereby ameliorate cardiac remodeling after I/R injury. Furthermore, we demonstrate that heme oxygenase 1 up-regulation in response to hypoxia and hypoxia/reoxygenation degrades heme and thereby induces iron overload and ferroptosis in the endoplasmic reticulum (ER) of cardiomyocytes. Collectively, ferroptosis triggered by GPx4 reduction and iron overload in the ER is distinct from MPT-driven necrosis in both in vivo phenotype and in vitro mechanism for I/R injury. The use of therapeutics targeting ferroptosis in conjunction with cyclosporine A can be a promising strategy for I/R injury..
4.	Tomonori Tadokoro, Masataka Ikeda, Ko Abe, Tomomi Ide, Hiroko Deguchi Miyamoto, Shun Furusawa, Kosei Ishimaru, Masatsugu Watanabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken-Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui, Ethoxyquin is a competent radical-trapping antioxidant for preventing ferroptosis in doxorubicin cardiotoxicity., Journal of cardiovascular pharmacology, 10.1097/FJC.0000000000001328, 2022.07, ABSTRACT: Doxorubicin (DOX) is an effective anti-cancer agent for various malignancies. Nevertheless, it has a side effect of cardiotoxicity, referred to as doxorubicin-induced cardiomyopathy (DIC), that is associated with a poorer prognosis. This cardiotoxicity limits the clinical use of DOX as a therapeutic agent for malignancies. Recently, ferroptosis, a form of regulated cell death induced by the accumulation of lipid peroxides, has been recognized as a major pathophysiology of DIC. Ethoxyquin is a lipophilic antioxidant widely used for food preservation and thus may be a potential therapeutic drug for preventing DIC. However, the efficacy of ethoxyquin against ferroptosis and DIC remains to be fully elucidated. Here, we investigated the inhibitory action of ethoxyquin against GPx4-deficient ferroptosis and its therapeutic efficacy against DOX-induced cell death in cultured cardiomyocytes and cardiotoxicity in a murine model of DIC. In cultured cardiomyocytes, ethoxyquin treatment effectively prevented GPx4-deficient ferroptosis. Ethoxyquin also prevented DOX-induced cell death, accompanied by the suppression of malondialdehyde (MDA) and mitochondrial lipid peroxides, which were induced by DOX. Furthermore, ethoxyquin significantly prevented DOX-induced cell death without any suppression of caspase cleavages representing apoptosis. In DIC mice, ethoxyquin treatment ameliorated cardiac impairments, such as contractile dysfunction and myocardial atrophy, and lung congestion. Ethoxyquin also suppressed serum lactate dehydrogenase and creatine kinase activities, decreased the levels of lipid peroxides such as MDA and acrolein, inhibited cardiac fibrosis, and reduced TUNEL-positive cells in the hearts of DIC mice. Collectively, ethoxyquin is a competent antioxidant for preventing ferroptosis in DIC and can be its prospective therapeutic drug..
5.	Yuta Nagatomi, Tomomi Ide, Tae Higuchi, Tomoyuki Nezu, Takeo Fujino, Takeshi Tohyama, Takuya Nagata, Taiki Higo, Toru Hashimoto, Shouji Matsushima, Keisuke Shinohara, Tomiko Yokoyama, Aika Eguchi, Ayumi Ogusu, Masataka Ikeda, Yusuke Ishikawa, Fumika Yamashita, Shintaro Kinugawa, Hiroyuki Tsutsui, Home-based cardiac rehabilitation using information and communication technology for heart failure patients with frailty, ESC HEART FAILURE, 10.1002/ehf2.13934, 2022.05, Aims Cardiac rehabilitation (CR) is an evidence-based, secondary preventive strategy that improves mortality and morbidity rates in patients with heart failure (HF). However, the implementation and continuation of CR remains unsatisfactory, particularly for outpatients with physical frailty. This study investigated the efficacy and safety of a comprehensive home-based cardiac rehabilitation (HBCR) programme that combines patient education, exercise guidance, and nutritional guidance using information and communication technology (ICT).Methods and results This study was a single-centre, open-label, randomized, controlled trial. Between April 2020 and November 2020, 30 outpatients with chronic HF (New York Heart Association II-III) and physical frailty were enrolled. The control group (n = 15) continued with standard care, while the HBCR group (n = 15) also received comprehensive, individualized CR, including ICT-based exercise and nutrition guidance using ICT via a Fitbit (R) device for 3 months. The CR team communicated with each patient in HBCR group once a week via the application messaging tool and planned the training frequency and intensity of training individually for the next week according to each patient's symptoms and recorded pulse data during exercise. Dietitians conducted a nutritional assessment and then provided individual nutritional advice using the picture-posting function of the application. The primary outcome was the change in the 6 min walking distance (6MWD). The participants' mean age was 63.7 +/- 10.1 years, 53% were male, and 87% had non-ischaemic heart disease. The observed change in the 6MWD was significantly greater in the HBCR group (52.1 +/- 43.9 m vs. -4.3 +/- 38.8 m; P
6.	Inoue T, Ide T, Yamato M, Yoshida M, Tsutsumi T, Andou M, Utsumi H, Tsutsui H, Sunagawa K, Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction, Free radical research, 2009.01.
7.	Yamato M, Shiba T, Yoshida M, Ide T, Seri N, Kudou W, Kinugawa S, Tsutsui H., Fatty acids increase the circulating levels of oxidative stress factors in mice with diet-induced obesity via redox changes of albumin, FEBS J., 274:3855-3863, 2007, 2008.07.
8.	Tsutsumi T., Ide T., Yamato M., Andou M., Shiba T., Utsumi H., Sunagawa K, Effect of anaesthesia-induced alterations in haemodynamics on in vivo kinetics of nitroxyl probes in electron spin resonance spectroscopy., Free Radic Res., 305-311, 2008.04.
9.	Tsutsumi T, Ide T, Yamato M, Kudou W, Andou M, Hirooka Y, Utsumi H, Tsutsui H, Sunagawa K, Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction., Cardiovasc Res., 713-721, 2008.03.
10.	Matsushima S, Ide T, Yamato M, Matsusaka H, Hattori F, Ikeuchi M, Kubota T, Sunagawa K, Hasegawa Y, Kurihara T, Oikawa S, Kinugawa S, Tsutsui H., Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice., Circulation, 113(14):1779-86., 2006.04.
11.	Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T, Kubota T, Fujiwara T, Hamasaki N, Takeshita A, Sunagawa K, Tsutsui H., Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction., Circulation., 10.1161/CIRCULATIONAHA.104.524835, 112, 5, 683-690, 112(5):683-90. , 2005.08.
12.	Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N, Takeshita A., Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes., Circulation. , 10.1161/01.CIR.0000055318.09997.1F, 107, 10, 1418-1423, 107(10):1418-23., 2003.03.
13.	Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, Utsumi H, Hamasaki N, Takeshita A., Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction., 88(5):529-35..

主要総説, 論評, 解説, 書評, 報告書等

全てを見る→

1.	Ide T, Seeking for the endogenous ligands for PPAR., Journal of Clinical Biochemistry and Nutrition, 2005.08.

主要学会発表等

全てを見る→

1.	Ide T, Mitochondria, oxidative stress and heart failure -Regulation of mitochondrial DNA as a strategy for cardiac remodeling-, The 25th Annual Meeting of the International Society of Heart Research Japanese Section (ISHR) , 2008.12.

特許出願・取得

特許出願件数 4件

特許登録件数 0件

所属学会名

日本腫瘍循環器学会

日本サルコイドーシス学会

欧州心臓病会議

日本生化学会

米国心臓学会

国際心臓研究会

日本酸化ストレス学会

日本ミトコンドリア学会

日本心臓リハビリテーション学会

日本心不全学会

日本内科学会

日本循環器学会

学協会役員等への就任

2018.09, 日本循環器学会, 教育研修/集中救急委員会委員.

2016.08, 日本心臓リハビリテーション学会, 評議員.

2016.04～2017.03, 日本循環器学会, 学術委員.

2010.05, 日本心不全学会, 幹事.

2010.05, 日本ミトコンドリア学会, 評議員.

2010.05, 国際心臓研究会（ISHR)日本部会, 評議員.

2007.04, 日本酸化ストレス学会, 評議員.

学会大会・会議・シンポジウム等における役割

2014.03.21～2014.03.23, 第78回日本循環器学会学術集会, 座長（Chairmanship）.

2014.04.19～2014.04.19, 西日本心臓血管研究会, 座長（Chairmanship）.

2013.07.04～2013.07.07, 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Special Session (Novel Strategy in the Treatment of Severe Heart Failure) organizer.

2013.07.04～2013.07.07, 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 座長（Chairmanship）.

2013.07.04～2013.07.07, 第35回国際生体医工学会議 , 座長（Chairmanship）.

2013.06.13～2013.06.14, 日本酸化ストレス学会, 座長（Chairmanship）.

2013.03.21～2013.03.21, 第86回日本薬理学会年会, 司会（Moderator）.

2013.01.10～2013.01.10, 福岡オートセットCS (ASV) clinical meeting, 座長（Chairmanship）.

2012.06.12～2012.06.12, 福岡オートセットCS (ASV) Clinical meeting, 座長（Chairmanship）.

2012.04.13～2012.04.14, 第49回日本臨床分子医学会学術集会, 座長（Chairmanship）.

2012.01.28～2012.01.28, 第296回日本内科学会九州地方会, 座長（Chairmanship）.

2011.12.01～2011.12.01, 福岡オートセットCS (ASV) clinical meeting, 座長（Chairmanship）.

2011.09.22～2011.09.23, The Cardiovascular System Dynamics Society, 座長（Chairmanship）.

2010.05～2010.05.21, 国際心臓研究会, 座長（Chairmanship）.

2008.03.28～2008.03.30, 日本循環器学会, 座長（Chairmanship）.

2013.10.25～2014.10.25, 日本サルコイドーシス学会, シンポジウム.

2013.10.20～2013.10.20, 九州大学大学院薬学研究院公開講座, 講演.

2013.09.25～2013.09.25, 有田町健康増進セミナー, 特別講演.

2013.09.09～2013.09.09, 久留米内科医会, 特別講演.

2013.08.10～2014.08.10, 東京心臓病理フォーラム, 特別講演.

2013.07.04～2013.07.07, 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 事務局.

2013.07.04～2013.07.07, 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Special Session Organizer.

2013.03.21～2013.03.23, 第86回　日本薬理学会学術集会, シンポジストおよびオーガナイザー.

2012.10.26～2012.10.27, 第29回国際心臓研究学会(ISHR)日本部会総会, 事務局.

2012.05.28～2012.05.29, 3th Brainstorming Medical Conference, 演者.

2011.05.16～2011.05.18, 第67回日本顕微鏡学会学術集会, シンポジスト.

2011.05.27～2011.05.29, 第11回日本抗加齢医学会総会, シンポジスト.

2011.09.02～2011.09.04, Molecular Cardiovascular Conference II, パネラー.

2011.09.21～2011.09.24, 第84回日本生化学会大会, シンポジスト.

2010.10.22～2010.10.23, The Cardiovascular System Dynamics Society, Chairperson.

2010.03.05～2010.03.07, 第74回　日本循環器学会学術集会 : Meet the expert, シンポジスト.

2009.03.03～2009.03.04, 第１回Free Radical School in Japan, シンポジスト.

2009.11.05～2009.11.06, 第62回　日本自律神経学会総会, シンポジスト.

2009.12.17～2009.12.19, 第9回　日本ミトコンドリア学会年会, シンポジスト.

2008.10.15～2008.10.17, Lipid Peroxidation 2008, symposist.

2008.12.05～2008.12.06, 国際心臓研究会（ISHR)第25回総会, シンポジスト：Cardiac Failure and Remodeling.

学術論文等の審査

年度	外国語雑誌査読論文数	日本語雑誌査読論文数	合計
2021年度	15		15
2019年度	25	1	26
2018年度	18		18
2017年度	19		19
2016年度	14		14
2015年度	20		20
2014年度	14		14
2013年度	12		12
2012年度	35	0	35
2011年度	19		19
2010年度	12		12
2009年度	27		27
2008年度	17		17
2007年度	5		5

研究奨励賞, 酸化ストレス学会, 2009.06.

上原記念生命科学財団　研究奨励賞, （財）上原記念生命科学財団, 2007.09.

第13回バイエル循環器病研究助成優秀賞, 日本心臓病財団, 2005.01.

Banyu Fellowship Award in Cardiovascular Medicine, 日本心臓病財団, 2000.09.

YIA最優秀賞, 日本循環器学会, 2000.03.

科学研究費補助金の採択状況(文部科学省、日本学術振興会)

2023年度～2027年度, 基盤研究(B), 代表, キラルアミノ酸メタボローム解析に基づく心不全の病態解明と治療法の確立.

2020年度～2022年度, 基盤研究(C), 代表, フェロトーシスを基軸とした心筋障害メカニズムの解明と治療法の開発.

2017年度～2019年度, 基盤研究(C), 代表, 脂質ラジカル可視化技術によるミトコンドリアー核連関の解明と心不全治療への応用.

2011年度～2013年度, 基盤研究(C), 代表, ミトコンドリアDNAの抗リモデリング効果の機序解明と新たな治療方法の確立.

2009年度～2010年度, 若手研究(B), 代表, 不全心におけるミトコンドリアＤＮＡの細胞内分子機構の解明と治療への応用.

2005年度～2006年度, 若手研究(B), 代表, 世界初のフリーラジカル二次元可視化技術を用いた動脈硬化の病態形成機序の解明.

競争的資金(受託研究を含む)の採択状況

2014年度～2016年度, 研究拠点形成費補助金(グローバルＣＯＥ) (文部科学省）, 認知症と心血管病の改善を図る迷走神経刺激効果を有する簡易トレーニングプログラムの開発とメカニズムの解明.

2005年度～2007年度, 第13回バイエル循環器病研究助成, 代表, ミトコンドリアDNA保護によるレドックス制御を介した新たな心不全治療の構築.

共同研究、受託研究(競争的資金を除く)の受入状況

2016.06～2020.06, 連携, 【研究題目】心筋リモデリングに及ぼす代謝調節の影響に関する研究.

2006.04～2008.03, 代表, ＴＦＡＭの細胞外分子としての役割に関する検討.

学内資金・基金等への採択状況

2009年度～2010年度, 女性研究者支援プログラム, 代表, 心不全におけるミトコンドリアの役割.


	※ 研究者情報全体を検索する場合は右端の「すべて」を選択して下さい。

九大関連コンテンツ