論文 - 丹野　雅也

Contribution of MLKL to the development of doxorubicin-induced cardiomyopathy and its amelioration by rapamycin.

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

Journal of pharmacological sciences   156 ( 1 ) 9 - 18  2024年09月  [国内誌]

　概要を見る

Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl+/- and Mlkl-/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.

DOI PubMed

Downregulation of Mitochondrial Fusion Protein Expression Affords Protection from Canonical Necroptosis in H9c2 Cardiomyoblasts

Yuki Toda, Sang-Bing Ong, Toshiyuki Yano, Atsushi Kuno, Hidemichi Kouzu, Tatsuya Sato, Wataru Ohwada, Yuki Tatekoshi, Toshifumi Ogawa, Masaki Shimizu, Masaya Tanno, Masato Furuhashi

International Journal of Molecular Sciences ( MDPI AG )  25 ( 5 ) 2905 - 2905  2024年03月

　概要を見る

Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.

DOI

心筋細胞のネクロプトーシスにおけるミトコンドリア動態の影響(Impact of Mitochondrial Dynamics on Necroptosis in Cardiomyocytes)

戸田 悠貴, 矢野 俊之, 久野 篤史, 丹野 雅也, 神津 英至, 佐藤 達也, 大和田 渉, 舘越 勇輝, 小川 俊史, 清水 将輝, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ080 - 3  2024年03月

ドキソルビシン誘発性心筋症の発症におけるMLKLの寄与(Contribution of MLKL to the Development of Doxorubicin-induced Cardiomyopathy)

清水 将輝, 大和田 渉, 矢野 俊之, 神津 英至, 佐藤 達也, 長南 新太, 小川 俊史, 戸田 悠貴, 久野 篤史, 丹野 雅也, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ073 - 1  2024年03月

Contribution of MLKL to the Development of Doxorubicin-induced Cardiomyopathy(タイトル和訳中)

清水 将輝, 大和田 渉, 矢野 俊之, 神津 英至, 佐藤 達也, 長南 新太, 小川 俊史, 戸田 悠貴, 久野 篤史, 丹野 雅也, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ073 - 1  2024年03月

Impact of Mitochondrial Dynamics on Necroptosis in Cardiomyocytes(タイトル和訳中)

戸田 悠貴, 矢野 俊之, 久野 篤史, 丹野 雅也, 神津 英至, 佐藤 達也, 大和田 渉, 舘越 勇輝, 小川 俊史, 清水 将輝, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  88回   PJ080 - 3  2024年03月

Role of AMP deaminase in diabetic cardiomyopathy

Tetsuji Miura, Hidemichi Kouzu, Masaya Tanno, Yuki Tatekoshi, Atsushi Kuno

Molecular and Cellular Biochemistry ( Springer Science and Business Media LLC )   2024年02月

DOI

Early Commencement and Long-Term Continuation of Tolvaptan Treatment Attenuate Functional Impairment of Renal Vasopressin V2 Receptors and Improve Clinical Outcomes in Patients with Heart Failure

Takahiro Noto, Arata Osanami, Nobutaka Nagano, Nobuaki Kokubu, Hidemichi Kouzu, Masaya Tanno

International Heart Journal ( International Heart Journal (Japanese Heart Journal) )  64 ( 1 ) 36 - 43  2023年03月  [査読有り]

DOI

BCKDH活性のダウンレギュレーションとAMPデアミナーゼとのアンカップリングが2型糖尿病性心臓における基質柔軟性の欠如を引き起こす(Downregulation of BCKDH Activity and Uncoupling from AMP Deaminase Underlie Substrate Inflexibility in Type 2 Diabetic Hearts)

小川 俊史, 神津 英至, 長南 新太, 清水 将輝, 戸田 悠貴, 大和田 渉, 佐藤 達也, 矢野 俊之, 久野 篤史, 丹野 雅也, 三浦 哲嗣, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   OJ03 - 2  2023年03月

Downregulation of BCKDH Activity and Uncoupling from AMP Deaminase Underlie Substrate Inflexibility in Type 2 Diabetic Hearts(タイトル和訳中)

小川 俊史, 神津 英至, 長南 新太, 清水 将輝, 戸田 悠貴, 大和田 渉, 佐藤 達也, 矢野 俊之, 久野 篤史, 丹野 雅也, 三浦 哲嗣, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   OJ03 - 2  2023年03月

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年02月  [招待有り]  [国内誌]

　概要を見る

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年02月  [査読有り]  [国内誌]

　概要を見る

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

Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts

Toshifumi Ogawa, Hidemichi Kouzu, Arata Osanami, Yuki Tatekoshi, Tatsuya Sato, Atsushi Kuno, Yugo Fujita, Shoya Ino, Masaki Shimizu, Yuki Toda, Wataru Ohwada, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Tetsuji Miura

Physiological Reports   11 ( 4 ) e15608  2023年02月  [査読有り]  [国際誌]

　概要を見る

Systemic branched-chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long-Evans-Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched-chain α-keto acid dehydrogenase (BCKDH), a rate-limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long-Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH-E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3-E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3-BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3-BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

DOI PubMed

Features and Outcomes of Histologically Proven Myocarditis With Fulminant Presentation

Koshiro Kanaoka, Kenji Onoue, Satoshi Terasaki, Tomoya Nakano, Michikazu Nakai, Yoko Sumita, Kinta Hatakeyama, Fumio Terasaki, Rika Kawakami, Yoshitaka Iwanaga, Yoshihiro Miyamoto, Yoshihiko Saito, Satoshi Yuda, Masaya Tanno, Toru Takahashi, Hisashi Yokoshiki, Masahiro Toba, Toshihisa Anzai, Toshiyuki Nagai, Takuma Sato, Takashi Takenaka, Seiji Yamazaki, Yuki Katagiri, Toshiharu Takeuchi, Kazuya Sugitatsu, Shigeo Kakinoki, Tomoaki Matsumoto, Kazushi Urasawa, Michinao Tan, Ichizo Tsujino, Mitsunori Kamigaki, Hirofumi Tomita, Kenji Hanada, Motoi Kushibiki, Akihiro Nakamura, Yoshihiro Morino, Takahito Nasu, Satoshi Yasuda, Hideaki Suzuki, Kaoru Iwabuchi, Kanako Tsuji, Shigeto Namiuchi, Tatsuya Komaru, Masahiro Yagi, Shoko Uematsu, Toshiaki Takahashi, Satoru Takeda, Toru Nakanishi, Masafumi Watanabe, Masahiro Wanezaki, Motoyuki Matsui, Shigeo Sugawara, Yasuchika Takeishi, Masayoshi Oikawa, Nobuo Komatsu, Satoshi Suzuki, Hiroshi Okamoto, Noriyuki Takeyasu, Daiki Akiyama, Yutaka Eki, Tsunekazu Kakuta, Tomoyo Sugiyama, Tomomi Koizumi, Koji Ueno, Kazuomi Kario, Mizuri Taki, Yuri Matsumoto, Takanori Yasu, Osamu Nishioka, Shigeto Naito, Makoto Murata, Shoichi Tange, Katsumi Kaneko, Makoto Muto, Hiroshi Inagaki, Shuichi Hasegawa, Eizo Tachibana, Wataru Atsumi, Masahiro Suzuki, Toshihiro Muramatsu, Yoshihiro Yamada, Isao Taguchi, Yoshiaki Fukuda, Akihiro Matsui, Junji Kanda, Koji Hozawa, Akihiko Matsumura, Wataru Shimizu, Takeshi Yamamoto, Issei Komuro, Masaru Hatano, Takanori Ikeda, Shunsuke Kiuchi, Taishiro Chikamori, Yasuyoshi Takei, Kyoko Soejima, Toshinori Minamishima, Hiroyuki Tanaka, Shigeo Shimizu, Masashi Kasao, Tadayuki Kadohira, Tohru Minamino, Kazunori Shimada, Hiroshi Iwata, Yukihiko Momiyama, Takashi Ashikaga, Toshihiro Nozato, Yasumasa Fujiwara, Kenji Inoue, Tetsuo Sasano, Junji Matsuda, Yasuhiro Ishii, Yuichi Ono, Kengo Tanabe, Yu Horiuchi, Toshiro Shinke, Yusuke Kodama, Masao Moroi, Yoshiyuki Yazaki, Taisuke Mizumura, Hiroshi Ohta, Yoshihiro Akashi, Nozomi Kotoku, Yuji Ikari, Mitsunori Maruyama, Yasuhiro Sato, Koichi Tamura, Masaaki Konishi, Hiroshi Suzuki, Mio Ebato, Kazuki Fukui, Kazuhiko Yumoto, Takamasa Iwasawa, Takeshi Kashimura, Kazuyoshi Takahashi, Yoshinobu Okada, Bunji Kaku, Kazuo Usuda, Michiro Maruyama, Tomoki Kameyama, Toshinori Higashikata, Akihiko Hodatsu, Kazuo Osato, Yoji Nagata, Koji Maeno, Kazuo Satake, Takao Sawanobori, Noboru Watanabe, Koichiro Kuwahara, Hirohiko Motoki, Hiroshi Kitabayashi, Kyuhachi Otagiri, Tsunesuke Kono, Daisuke Yamagishi, Yoshikazu Yazaki, Toshiyuki Noda, Itsuro Morishima, Naoki Watanabe, Shinichiro Tanaka, Tomoya Onodera, Ryuzo Nawada, Akinori Watanabe, Masaki Matsunaga, Satoru Suwa, Hiroshi Sakamoto, Hiroki Sakamoto, Takeshi Aoyama, Norio Kanamori, Masahiro Muto, Yuichiro Maekawa, Hayato Ohtani, Yukio Ozaki, Kenshin Naruse, Kenji Takemoto, Haruo Kamiya, Takeshi Suzuki, Yasushi Tomita, Susumu Suzuki, Ryosuke Kametani, Hidekazu Aoyama, Hiroyuki Osanai, Ken Harada, Kenji Kada, Tomoaki Saeki, Koichi Kobayashi, Yasuhiro Ogawa, Akihiro Terasawa, Masanori Shinoda, Mitsutoshi Oguri, Kiyokazu Shimizu, Akinori Sawamura, Atsushi Sugiura, Kosuke Hattori, Shinji Mokuno, Kazuhisa Kondo, Kaoru Dohi, Keishi Moriwaki, Atsunobu Kasai, Tetsuya Nakakuki, Kazuaki Kaitani, Toshikazu Jinnai, Takashi Yamamoto, Hiroyuki Kurata, Atsuyuki Wada, Masaharu Akao, Yasuhiro Hamatani, Kazuya Ishibashi, Yoshiki Akakabe, Yasuhide Asaumi, Hideo Matama, Yasushi Sakata, Hidetaka Kioka, Hiroshi Takaishi, Yoshitaka Iwanaga, Toru Takase, Mitsuo Matsuda, Fumi Sato, Shinji Hasegawa, Kenichi Ishigami, Minoru Ichikawa, Takashi Takagi, Moriaki Inoko, Masaaki Hoshiga, Shuichi Fujita, Yoshihiro Takeda, Takahiko Kawarabayashi, Hideyuki Takaoka, Kenji Nakajima, Tadashi Yuguchi, Tatsuya Kawasaki, Yukinori Shinoda, Yukihito Sato, Masaharu Ishihara, Yuki Matsumoto, Hiroya Kawai, Tomofumi Takaya, Kouki Matsuo, Toshiaki Mano, Kenichi Hirata, Eriko Hisamatsu, Nobutaka Inoue, Koichi Tamita, Naoki Mukohara, Hisashi Shimoyama, Toru Miyajima, Toshihiro Tamura, Yodo Tamaki, Megumi Suzuki, Ryoji Yokota, Manabu Horii, Kazuo Yamanaka, Hiroyuki Kawata, Yukihiro Hashimoto, Yasuki Nakada, Hitoshi Nakagawa, Tomoya Ueda, Taku Nishida, Ayako Seno, Makoto Watanabe, Takashi Akasaka, Takashi Tanimoto, Mamoru Toyofuku, Kazuhiro Yamamoto, Yoshiharu Kinugasa, Masayuki Hirai, Hiroshi Nasu, Kinya Shirota, Tsuyoshi Oda, Takefumi Oka, Kazushige Kadota, Masanobu Ohya, Hiroshi Ito, Kazufumi Nakamura, Soichiro Ogura, Soichiro Fuke, Shiro Uemura, Hiromi Matsubara, Atsuyuki Watanabe, Nobuyuki Morishima, Yasuki Kihara, Takayuki Hidaka, Hironori Ueda, Yujiro Ono, Yuji Muraoka, Miyo Hatanari, Yoshinori Miyamoto, Keigo Dote, Masaya Kato, Masafumi Yano, Mamoru Mochizuki, Yasuhiro Ikeda, Hiroyuki Fujinaga, Shinobu Hosokawa, Masataka Sata, Koji Yamaguchi, Naoko Aki, Tetsuo Minamino, Yuichi Miyake, Yuichiro Takagi, Masayuki Doi, Yoshio Taketani, Hideki Okayama, Tatsuya Shigematsu, Akinori Higaki, Osamu Yamaguchi, Shinji Inaba, Shuntaro Ikeda, Kazuya Kawai, Hiroaki Kitaoka, Toru Kubo, Kenji Ando, Kaoru Inui, Yoshihiro Fukumoto, Kensuke Hori, Takehiro Homma, Tomohiro Kawasaki, Masahiro Mohri, Masaki Fujiwara, Hiroyuki Tsutsui, Tomomi Ide, Shin-Ichiro Miura, Takashi Kuwano, Hideki Shimomura, Toshiaki Kadokami, Masanao Taba, Katsuhiro Kondou, Toru Kubota, Daisuke Nagatomo, Yasushi Mukai, Ryuichi Matsukawa, Hideki Tashiro, Mitsuhiro Shimomura, Koji Maemura, Hiroaki Kawano, Koji Oku, Toshihiko Yamasa, Yoshihisa Kizaki, Tomohiro Sakamoto, Yudai Tamura, Teruhiko Ito, Kazuteru Fujimoto, Kenichi Tsujita, Seiji Takashio, Hirofumi Kurokawa, Naohiko Takahashi, Shotaro Saito, Masaya Arikawa, Yoshisato Shibata, Kensaku Nishihira, Toshihiro Tsuruda, Masahiro Sonoda, Nobuhiko Atsuchi, Mitsuru Ohishi, Koji Higuchi, Masaaki Miyata, Naoya Oketani, Yoshinori Akimoto, Tomohiro Asahi, Minoru Wake

Circulation ( Ovid Technologies (Wolters Kluwer Health) )  146 ( 19 ) 1425 - 1433  2022年11月  [査読有り]

　概要を見る

Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion (<40%) on admission, and ventricular tachycardia or fibrillation on admission day were associated with worse 90-day survival. Severe histologic damage (damaged cardiomyocytes comprising ≥50% of the total cardiomyocytes) was associated with a worse 90-day prognosis in patients with lymphocytic myocarditis. Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

DOI

今月の症例 脳梗塞発症を契機に診断されたLoeffler心内膜心筋炎を伴う好酸球性多発血管炎性肉芽腫症の1例

大和田 渉, 矢野 俊之, 赤澤 史子, 神津 英至, 續 太郎, 宮森 大輔, 西川 諒, 永野 伸卓, 小山 雅之, 村中 敦子, 丹野 雅也

日本内科学会雑誌 ( (一社)日本内科学会 )  111 ( 8 ) 1580 - 1586  2022年08月

　概要を見る

60歳女性。気管支喘息の加療中に脳梗塞が生じ、その際に好酸球増多が確認され、精査加療目的で当院へ転院となった。入院時、好酸球増多、トロポニンT上昇がみられ、心エコーでは左室駆出率の低下、左室流出路に可動性血栓が認められた。また、心臓造影MRIでは内膜主体の遅延造影が認められ、心筋生検では線維化所見が認められた。以上、これらの所見を踏まえて、本症例はLoeffler心内膜心筋炎を伴う好酸球性多発血管炎性肉芽腫症と診断された。治療としてステロイドと抗凝固療法を行った結果、好酸球数とトロポニンTの低下、血栓消失が得られたが、左室駆出率は改善しなかった。

Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

Yugo Fujita, Toshiyuki Yano, Hiromitsu Kanamori, Daigo Nagahara, Atsuko Muranaka, Hidemichi Kouzu, Atsushi Mochizuki, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Naoyuki Kamiyama, Marenao Tanaka, Atsushi Kuno, Masaya Tanno, Tetsuji Miura

ESC Heart Failure ( Wiley )   2022年07月  [査読有り]

DOI

Insulin Resistance ― Beginning of the Road to Coronary Microvascular Dysfunction and Beyond ―

Masaya Tanno, Arata Osanami

Circulation Journal ( Japanese Circulation Society )  86 ( 5 ) 874 - 876  2022年04月  [査読有り]

DOI

Ubiquitin-dependent rapid degradation conceals a cell-protective function of cytoplasmic SIRT3 against oxidative stress.

Takashi Hayashi, Takashi Matsushita, Shin Hisahara, Naotoshi Iwahara, Atsushi Kuno, Risa Kunimoto, Ryusuke Hosoda, Masaya Tanno, Shun Shimohama, Yoshiyuki Horio

Journal of biochemistry   171 ( 2 ) 201 - 213  2022年02月  [査読有り]  [国際誌]

　概要を見る

SIRT3 is an NAD+-dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mitochondria and cytoplasm in the brain and cultured neural cells. However, expression levels of SIRT3ct in COS cells transfected with SIRT3ct cDNA were much lower than those of SIRT3mt. We found that SIRT3ct but not SIRT3mt was promptly degraded by ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by ubiquitination of NH2-terminal methionine and partly by that of lysine residues of SIRT3ct. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 treatment promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. Overexpression of SIRT3ct decreased cell death caused by H2O2 at levels similar to those achieved by overexpression of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death caused by amyloid-β (Aβ), and overexpression of SIRT3ct suppressed the toxic function of Aβ in PC12 cells. These results indicate that SIRT3ct promotes cell survival under physiological and pathological conditions.

DOI PubMed

Reduction in GLP-1 secretory capacity may be a novel independent risk factor of coronary artery stenosis.

Chihiro Nagase, Masaya Tanno, Hidemichi Kouzu, Takayuki Miki, Junichi Nishida, Naoto Murakami, Nobuaki Kokubu, Nobutaka Nagano, Ryo Nishikawa, Nobuhiro Yoshioka, Tohru Hasegawa, Hiroyuki Kita, Akihito Tsuchida, Hirofumi Ohnishi, Tetsuji Miura

Scientific reports   11 ( 1 ) 15578 - 15578  2021年08月  [査読有り]  [国際誌]

　概要を見る

Multiple factors regulate glucagon-like peptide-1 (GLP-1) secretion, but a group of apparently healthy subjects showed blunted responses of GLP-1 secretion in our previous study. In this study, we examined whether the reduction in GLP-1 secretory capacity is associated with increased extent of coronary artery stenosis in non-diabetic patients. Non-diabetic patients who were admitted for coronary angiography without a history of coronary interventions were enrolled. Coronary artery stenosis was quantified by Gensini score (GS), and GS ≥ 10 was used as an outcome variable based on its predictive value for cardiovascular events. The patients (mean age, 66.5 ± 8.8 years; 71% males, n = 173) underwent oral 75 g-glucose tolerant tests for determination of glucose, insulin and active GLP-1 levels. The area under the curve of plasma active GLP-1 (AUC-GLP-1) was determined as an index of GLP-1 secretory capacity. AUC-GLP-1 was not correlated with fasting glucose, AUC-glucose, serum lipids or indices of insulin sensitivity. In multivariate logistic regression analysis for GS ≥ 10, AUC-GLP-1 < median, age and hypertension were selected as explanatory variables, though fasting GLP-1 level was not selected. The findings suggest that reduction in GLP-1 secretory capacity is a novel independent risk factor of coronary stenosis.

DOI PubMed

Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model.

Satoru Shibata, Norihito Moniwa, Atsushi Kuno, Ayumu Kimura, Wataru Ohwada, Hirohito Sugawara, Yufu Gocho, Marenao Tanaka, Toshiyuki Yano, Masato Furuhashi, Masaya Tanno, Takayuki Miki, Tetsuji Miura

Clinical and experimental nephrology   25 ( 7 ) 708 - 717  2021年07月  [査読有り]  [国内誌]

　概要を見る

BACKGROUND: The risk of contrast-induced nephropathy (CIN) is high in patients with chronic kidney disease (CKD). However, the mechanism of CIN in CKD is not fully understood. Here, we prepared a clinically relevant model of CIN and examined the role of necroptosis, which potentially cross-talks with autophagy, in CIN. METHODS: In Sprague-Dawley rats, CKD was induced by subtotal nephrectomy (SNx, 5/6 nephrectomy) 4 weeks before induction of CIN. CIN was induced by administration of a contrast medium (CM), iohexol, following administration of indomethacin and N-omega-Nitro-L-arginine methyl ester. Renal function and tissue injuries were assessed 48 h after CM injection. RESULTS: Serum creatinine (s-Cre) and BUN were increased from 0.28 ± 0.01 to 0.52 ± 0.02 mg/dl and from 15.1 ± 0.7 to 29.2 ± 1.2 mg/dl, respectively, after SNx alone. CM further increased s-Cre and BUN to 0.69 ± 0.03 and 37.2 ± 2.1, respectively. In the renal tissue after CM injection, protein levels of receptor-interacting serine/threonine-protein kinase (RIP) 1, RIP3, cleaved caspase 3, and caspase 8 were increased by 64 ~ 212%, while there was reduction in LC3-II and accumulation of p62. Necrostatin-1, an RIP1 inhibitor, administered before and 24 h after CM injection significantly suppressed elevation of s-Cre, BUN and urinary albumin levels, kidney injury molecule-1 expression and infiltration of CD68-positive macrophages in renal tissues after CM injection. CONCLUSION: The results suggest that necroptosis of proximal tubular cells contributes to CIN in CKD and that suppression of protective autophagy by pro-necroptotic signaling may also be involved.

DOI PubMed

糖尿病腎の心腎症候群type 1への感受性増加におけるTLRs/NOXsシグナル伝達とオートファジー障害の影響(Detrimental Roles of TLRs/NOXs Signaling and Impaired Autophagy in Increased Susceptibility of the Diabetic Kidney to Type 1 Cardiorenal Syndrome)

Kuno Atsushi, Sato Tatsuya, Kouzu Hidemichi, Yano Toshiyuki, Tanno Masaya, Miura Tetsuji

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  85回   PL09 - 1  2021年03月

ミトコンドリア関連ER膜および細胞質におけるAMPデアミナーゼの上昇は糖尿病心の圧負荷による心機能障害に大きく寄与する(Upregulated AMP Deaminase in Mitochondria-associated ER Membranes and Cytosol Distinctively Contributes to Pressure Overload-induced Cardiac Dysfunction in Diabetic Hearts)

Tanno Masaya, Osanami Arata, Kouzu Hidemichi, Ogawa Toshifumi, Kuno Atsushi, Miura Tetsuji

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  85回   SS14 - 4  2021年03月

院外心停止蘇生後患者における血液凝固/線溶異常の予後的意義(Prognostic Value of Abnormalities in the Coagulation/Fibrinolysis Status in Patients after Resuscitation from Out-of-Hospital Cardiac Arrest)

中田 潤, 國分 宣明, 永野 伸卓, 西川 諒, 高橋 遼, 岸上 直広, 大友 俊作, 小山 雅之, 丹野 雅也, 三浦 哲嗣

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  85回   OJ26 - 6  2021年03月

Mitochondrial associated ER membraneにおけるAMPD3の役割とミトコンドリア膜透過性遷移の閾値制御(Role of AMPD3 in Mitochondria-associated ER Membranes in Regulation of Threshold for Mitochondrial Permeability Transition)

Osanami Arata, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Yano Toshiyuki, Ogawa Toshifumi, Sato Tatsuya, Miura Tetsuji

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  85回   OE080 - 6  2021年03月

AMPデアミナーゼの細胞内局在化とXORによるROS生成におけるCytosolic AMPDの役割(Intracellular Localization of AMP Deaminase and a Role of Cytosolic AMPD in XOR-mediated ROS Production)

Osanami Arata, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Yano Toshiyuki, Ogawa Toshifumi, Sato Tatsuya, Miura Tetsuji

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  85回   OE081 - 6  2021年03月

Prognostic Value of Abnormalities in the Coagulation/Fibrinolysis Status in Patients after Resuscitation from Out-of-Hospital Cardiac Arrest(和訳中)

中田 潤, 國分 宣明, 永野 伸卓, 西川 諒, 高橋 遼, 岸上 直広, 大友 俊作, 小山 雅之, 丹野 雅也, 三浦 哲嗣

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  85回   OJ26 - 6  2021年03月

Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload.

Yusuke Igaki, Masaya Tanno, Tatsuya Sato, Hidemichi Kouzu, Toshifumi Ogawa, Arata Osanami, Toshiyuki Yano, Atsushi Kuno, Takayuki Miki, Takashi Nakamura, Tetsuji Miura

Journal of molecular and cellular cardiology   154   21 - 31  2021年02月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: We previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats. METHODS AND RESULTS: Pressure-volume loop analysis revealed that pressure overloading by phenylephrine infusion induced severer left ventricular diastolic dysfunction (tau: 14.7 ± 0.8 vs 12.5 ± 0.7 msec, left ventricular end-diastolic pressure: 18.3 ± 1.5 vs 12.2 ± 1.3 mmHg, p < 0.05) and ventricular-arterial uncoupling in OLETF than in LETO, non-diabetic rats, though the baseline parameters were comparable in the two groups. While the pressure overload did not affect AMPD activity, it increased XOR activity both in OLETF and LETO, with OLETF showing significantly higher XOR activity than that in LETO (347.2 ± 17.9 vs 243.2 ± 6.1 μg/min/mg). Under the condition of pressure overload, myocardial ATP level was lower, and levels of xanthine and uric acid were higher in OLETF than in LETO. Addition of exogenous inosine, a product of AMP deamination, to the heart homogenates augmented XOR activity. OLETF showed 68% higher tissue ROS levels and 47% reduction in mitochondrial state 3 respiration compared with those in LETO. Overexpression of AMPD3 in H9c2 cells elevated levels of hypoxanthine and ROS and reduced the level of ATP. Inhibition of XOR suppressed the production of tissue ROS and mitochondrial dysfunction and improved ventricular function under the condition of pressure overload in OLETF. CONCLUSIONS: The results suggest that increases in the activity of XOR and the formation of XOR substrates by upregulated AMPD contribute to ROS-mediated diastolic ventricular dysfunction at the time of increased cardiac workload in diabetic hearts.

DOI PubMed

Activation of the angiotensin II receptor promotes autophagy in renal proximal tubular cells and affords protection from ischemia/reperfusion injury

Hirohito Sugawara, Norihito Moniwa, Atsushi Kuno, Wataru Ohwada, Arata Osanami, Satoru Shibata, Yukishige Kimura, Koki Abe, Yufu Gocho, Masaya Tanno, Tetsuji Miura

Journal of Pharmacological Sciences ( Elsevier BV )  145 ( 2 ) 187 - 197  2021年02月  [査読有り]

DOI

経口ブドウ糖負荷試験で診断し得た機能性低血糖症の1例

寺沢 誠, 長南 新太, 佐藤 達也, 原田 なお, 川原田 航, 箱崎 頌平, 後町 結, 茂庭 仁人, 矢野 俊之, 古橋 眞人, 丹野 雅也, 三浦 哲嗣

日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  96 ( 3 ) 596 - 596  2021年01月

Distinct intra-mitochondrial localizations of pro-survival kinases and regulation of their functions by DUSP5 and PHLPP-1

Wataru Ohwada, Masaya Tanno, Toshiyuki Yano, Sang-Bing Ong, Koki Abe, Tatsuya Sato, Atsushi Kuno, Takayuki Miki, Hirohito Sugawara, Yusuke Igaki, Tetsuji Miura

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( Elsevier BV )  1866 ( 10 ) 165851 - 165851  2020年10月  [査読有り]

DOI

非専門医の外来診療における慢性合併症評価率の年次変化

小川 俊史, 佐藤 達也, 三木 隆幸, 東浦 幸村, 伊野 祥哉, 矢野 俊之, 古橋 眞人, 神津 英至, 丹野 雅也, 斎藤 重幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  63 ( Suppl.1 ) S - 204  2020年08月

非虚血性拡張型心筋症において核内および介在板に局在するnecroptosisの実行因子リン酸化MLKLは各々独立して働いている(Phosphorylated MLKL, an Executor of Necroptosis, Localized in the Nucleus and Intercalated Disc Plays Distinct Roles in Nonischemic Dilated Cardiomyopathy)

Fujita Yugo, Yano Toshiyuki, Nagano Nobutaka, Nishikawa Ryo, Kamiyama Naoyuki, Fujito Takefumi, Mochizuki Atsushi, Koyama Masayuki, Kouzu Hidemichi, Muranaka Atsuko, Nagahara Daigo, Tanno Masaya, Miki Takayuki, Miura Tetsuji

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  84回   OE61 - 5  2020年07月

ドキソルビシン誘発性心筋症の発症には鉄結合タンパク質ではなく遊離鉄のミトコンドリアへの蓄積が関与している可能性がある(Accumulation of Free Iron, but not Protein-bound Iron, in Mitochondria may Contribute to Development of Doxorubicin-induced Cardiomyopathy)

Sato Tatsuya, Kikuchi Tatsuya, Yano Toshiyuki, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Miura Tetsuji

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  84回   PE48 - 7  2020年07月

糖尿病外来診療における慢性合併症評価の実態調査

小川 俊史, 佐藤 達也, 東浦 幸村, 伊野 祥哉, 矢野 俊之, 古橋 眞人, 丹野 雅也, 三木 隆幸, 斎藤 重幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  63 ( 5 ) 356 - 356  2020年05月

mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation

Abe K, Yano T, Tanno M, Miki T, Kuno A, Sato T, Kouzu H, Nakata K, Ohwada W, Kimura Y, Sugawara H, Shibat S, Igaki Y, Ino S, Miura T

BBA Molecular Basis of Disease   1865 ( 12 ) 165552  2019年12月  [査読有り]

DOI PubMed

心不全と心腎連関における髄質集合管バソプレシンV2受容体の役割 BOREAS-ADHFレジストリ解析結果より

丹野 雅也, 永野 伸卓, 能登 貴弘, 長南 新太, 神津 英至, 三浦 哲嗣

日本心臓病学会学術集会抄録 ( (一社)日本心臓病学会 )  67回   SS - 3  2019年09月

Canagliflozin, an SGLT2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats.

Kimura Y, Kuno A, Tanno M, Sato T, Ohno K, Shibata S, Nakata K, Sugawara H, Abe K, Igaki Y, Yano T, Miki T, Miura T

Journal of Diabetes Investigation   10 ( 4 ) 933 - 946  2019年07月  [査読有り]

DOI PubMed

mTORC1活性阻害はRIP1の抑制的リン酸化により心筋細胞のネクロプトーシスを抑制する

矢野 俊之, 安倍 功記, 佐藤 達也, 神津 英至, 久野 篤史, 丹野 雅也, 三木 隆幸, 三浦 哲嗣

日本循環制御医学会総会プログラム・抄録集 ( 日本循環制御医学会 )  40回   63 - 63  2019年06月

Accuracy of flash glucose monitoring in insulin-treated patients with type 2 diabetes.

Tatsuya Sato, Hiroto Oshima, Kei Nakata, Yukishige Kimura, Toshiyuki Yano, Masato Furuhashi, Masaya Tanno, Takayuki Miki, Tetsuji Miura

Journal of diabetes investigation   10 ( 3 ) 846 - 850  2019年05月  [査読有り]  [国内誌]

　概要を見る

The present study evaluated the accuracy of interstitial glucose measurements by flash glucose monitoring (FGM) and continuous glucose monitoring (CGM). Five diabetes patients simultaneously underwent FGM (FreeStyle Libre Pro) and CGM (iPro™2), and their glucose levels were compared with venous blood and capillary blood glucose levels. The range of daily venous blood glucose levels (30 measurements) was 70-245 mg/dL, with a median of 138 mg/dL. There were good correlations of glucose levels measured by FGM (r2  = 0.90, mean absolute relative difference 8.2 ± 5.6%), CGM (r2  = 0.86, mean absolute relative difference 9.2 ± 9.1%) and capillary blood (r2  = 0.87, mean absolute relative difference 7.2 ± 7.2%) with venous blood glucose levels. The accuracy of FGM measurements was also shown against CGM, with 99.9% of the FGM values (1,279 measurements) being within the Parkes error grid zones A and B. The results suggest that the accuracy of FGM is similar to that of CGM, and that FGM is a useful tool for determining daily glucose profile.

DOI PubMed

AKIに対するアンジオテンシンII前投与による腎保護効果はAT1およびMas受容体減少の軽減とautophagy活性化を伴う

菅原 浩仁, 茂庭 仁人, 柴田 智, 矢野 俊之, 久野 篤史, 丹野 雅也, 三木 隆幸, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  61 ( 3 ) 285 - 285  2019年05月

糖尿病の外来診療における慢性合併症評価実態の検討

伊野 祥哉, 中田 圭, 東浦 幸村, 佐藤 達也, 矢野 俊之, 古橋 眞人, 丹野 雅也, 三木 隆幸, 斎藤 重幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  62 ( Suppl.1 ) S - 306  2019年04月

Empagliflozin, an SGLT2 inhibitor, reduced the mortality rate after acute myocardial infarction with modification of cardiac metabolomes and anti-oxidants in diabetic rats.

Oshima H, Miki T, Kuno A, Mizuno M, Sato T, Tanno M, Yano T, Nakata K, Kimura Y, Abe K, Ohwada W, Miura T

The Journal of pharmacology and experimental therapeutics   368 ( 3 ) 524 - 534  2019年03月  [査読有り]

DOI PubMed

JDS-JCSジョイントシンポ(Controversy or Debate)-"Stop DM for Stop CVD"生命予後改善のための糖尿病管理とは 心血管イベントリスクの高い糖尿病患者を検出するためのECG検査の重要性とSGLT2阻害薬によって得られる利点(Importance of ECG Examination to Detect High Risk Diabetic Patients for Cardiovascular Events and Their Benefit Afforded by SGLT2 Inhibitors)

三木 隆幸, 佐藤 達也, 大西 浩文, 矢野 俊之, 中田 圭, 丹野 雅也, 三浦 哲嗣

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  83回   SY12 - 3  2019年03月

エピジェネティクスにおけるNon-coding RNA 糖尿病性心筋症の重要因子であるAMP deaminaseの新規microRNA介在性制御(Non-coding RNAs as Regulators in Epigenetics Novel microRNA-mediated Regulation of AMP Deaminase, a Key Player in Diabetic Cardiomyopathy)

Tanno Masaya, Tatekoshi Yuki, Kouzu Hidemichi, Kuno Atsushi, Yano Toshiyuki, Miki Takayuki, Miura Tetsuji

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  83回   SY14 - 4  2019年03月

バソプレシンV2受容体機能が維持された心不全患者において、トルバプタンの早期開始は長期予後を改善する

能登 貴弘, 丹野 雅也, 永野 伸卓, 長南 新太, 神津 英至, 三浦 哲嗣

日本内科学会雑誌 ( (一社)日本内科学会 )  108 ( Suppl. ) 265 - 265  2019年02月

【心不全(第2版)上-最新の基礎・臨床研究の進歩-】心不全の基礎研究 心不全の分子機序 心筋リモデリング DNA・転写制御障害 Sirtuin

丹野 雅也, 久野 篤史

日本臨床 ( (株)日本臨床社 )  76 ( 増刊9 心不全(上) ) 325 - 330  2018年12月

Does p53 Inhibition Suppress Myocardial Ischemia-Reperfusion Injury?

Yano T, Abe K, Tanno M, Miki T, Kuno A, Miura T, Steenbergen C

Journal of cardiovascular pharmacology and therapeutics   23 ( 4 ) 350 - 357  2018年07月  [査読有り]

DOI PubMed

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts.

Mizuno M, Kuno A, Yano T, Miki T, Oshima H, Sato T, Nakata K, Kimura Y, Tanno M, Miura T

Physiological Reports   6 ( 12 ) e13741  2018年06月  [査読有り]

DOI PubMed

Translational regulation by miR-301b upregulates AMP deaminase in diabetic hearts.

Tatekoshi Y, Tanno M, Kouzu H, Abe K, Miki T, Kuno A, Yano T, Ishikawa S, Ohwada W, Sato T, Niinuma T, Suzuki H, Miura T

Journal of Molecular and Cellular Cardiology   119   138 - 146  2018年06月  [査読有り]

DOI PubMed

アンジオテンシンIIの短期投与は尿細管autophagyを活性化し,急性腎障害を軽減する

菅原 浩仁, 茂庭 仁人, 柴田 智, 木村 幸滋, 山下 智久, 矢野 俊之, 久野 篤史, 丹野 雅也, 三木 隆幸, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  60 ( 3 ) 460 - 460  2018年04月

糖尿病が重症急性心不全の予後に及ぼす影響

柴田 智, 三木 隆幸, 山下 智久, 菅原 浩仁, 佐藤 達也, 大島 洸人, 矢野 俊之, 丹野 雅也, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  61 ( Suppl.1 ) S - 426  2018年04月

Distinct impacts of sleep-disordered breathing on glycemic variability in patients with and without diabetes mellitus

Kei Nakata, Takayuki Miki, Masaya Tanno, Hirofumi Ohnishi, Toshiyuki Yano, Atsuko Muranaka, Tatsuya Sato, Hiroto Oshima, Yuki Tatekoshi, Masashi Mizuno, Koki Abe, Tetsuji Miura

PLOS ONE ( PUBLIC LIBRARY SCIENCE )  12 ( 12 ) e0188689  2017年12月  [査読有り]

　概要を見る

Background Sleep-disordered breathing (SDB) is highly prevalent in patients with diabetes mellitus (DM) and heart failure (HF) and contributes to poor cardiovascular outcomes. Enlarged glycemic variability (GV) is a risk factor of cardiac events independently of average blood glucose level, but the influence of SDB on GV is uncertain. In this study, we examined whether the impact of SDB on GV is modified by the presence of DM with or without HF. Methods and results Two hundred three patients (67.5 +/- 14.1 [ SD] years old, 132 males) who were admitted to our institute for examination or treatment of DM and/or HF underwent continuous glucose monitoring and polysomnography. Both HbA1c (8.0 +/- 2.0 vs. 5.7 +/- 0.4%) and mean amplitude of glycemic excursion (MAGE, median: 95.5 vs. 63.5 mg/dl) were significantly higher in a DM group (n = 100) than in a non-DM group (n = 103), but apnea-hypopnea index (AHI: 29.0 +/- 22.7 vs. 29.3 +/- 21.5) was similar in the two groups. AHI was correlated with log MAGE in the non-DM group but not in the DM group, and multivariate regression analysis revealed that AHI was an independent variable for log MAGE in the non-DM group but not in the DM group. We then divided the non-DM patients into two subgroups according to BNP level (100 pg/ml). AHI was positively correlated with log MAGE (r = 0.74, p<0.001) in the non-DM low-BNP subgroup, but such a correlation was not found in the non-DM high-BNP subgroup. Continuous positive airway pressure (CPAP) reduced MAGE from 75.3 to 53.0 mg/dl in the non-DM group but did not reduce MAGE in the DM group. Conclusion Severity of SDB was associated with higher GV, but DM as well as HF diminished the contribution of SDB to GV. Treatment with CPAP was effective for reduction of GV only in patients without DM.

DOI PubMed

Diabetes increases the susceptibility to acute kidney injury after myocardial infarction through augmented activation of renal Toll-like receptors in rats

Kouhei Ohno, Atsushi Kuno, Hiromichi Murase, Shingo Muratsubaki, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Satoko Ishikawa, Tomohisa Yamashita, Tetsuji Miura

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY ( AMER PHYSIOLOGICAL SOC )  313 ( 6 ) H1130 - H1142  2017年12月  [査読有り]

　概要を見る

Acute kidney injury (AKI) after acute myocardial infarction (MI) worsens the prognosis of MI patients. Although type 2 diabetes mellitus (DM) is a major risk factor of AKI after MI, the underlying mechanism remains unclear. Here, we examined the roles of renal Toll-like receptors (TLRs) in the impact of DM on AKI after MI. MI was induced by coronary artery ligation in Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a rat DM model, and Long-Evans-Tokushima-Otsuka (LETO) rats, nondiabetic controls. Sham-operated rats served as no-MI controls. Renal mRNA levels of TLR2 and myeloid differentiation factor 88 (MyD88) were significantly higher in sham-operated OLETF rats than in sham-operated LETO rats, although levels of TLR1, TLR3, and TLR4 were similar. At 12 h after MI, protein levels of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the kidney were elevated by 5.3-and 4.0-fold, respectively, and their mRNA levels were increased in OLETF but not LETO rats. The increased KIM-1 and NGAL expression levels after MI in the OLETF kidney were associated with upregulated expression of TLR1, TLR2, TLR4, MyD88, IL-6, TNF-alpha. chemokine (C-C motif) ligand 2. and transforming growth factor-beta(1) and also with activation of p38 MAPK, JNK, and NF-kappa B. Cu-CPT22, a TLR1/TLR2 antagonist, administered before MI significantly suppressed MI-induced upregulation of KIM-1, TLR2, TLR4, MyD88, and chemokine (C-C motif) ligand 2 levels and activation of NF-kappa B, whereas NGAL levels and IL-6 and TNF-alpha expression levels were unchanged. The results suggest that DM increases the susceptibility to AKI after acute MI by augmented activation of renal TLRs and that TLR1/TLR2-mediated signaling mediates KIM-1 upregulation after MI. NEW & NOTEWORTHY This is the first report to demonstrate the involvement of Toll-like recpetors (TLRs) in diabetes-induced susceptibility to acute kidney injury after acute myocardial infarction. We propose that the TLR1/TLR2 heterodimer may be a new therapeutic. target for the prevention of acute kidney injury in diabetic patients.

DOI PubMed

Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes

T. Sato, T. Miki, H. Ohnishi, T. Yamashita, A. Takada, T. Yano, M. Tanno, A. Tsuchida, T. Miura

DIABETIC MEDICINE ( WILEY )  34 ( 10 ) 1367 - 1371  2017年10月  [査読有り]

　概要を見る

AimsTo test the hypothesis that treatment with a sodium-glucose co-transporter-2 inhibitor would reverse ventricular repolarization heterogeneity, a predictor of cardiovascular mortality, in people with Type 2 diabetes. MethodsWe retrospectively analysed changes in indices of ventricular repolarization before and after treatment with a sodium-glucose co-transporter-2 inhibitor in 46 people with Type 2 diabetes. ResultsSodium-glucose co-transporter-2 inhibitor treatment reduced HbA(1c) concentration [6213 mmol/mol (7.71.2%) vs 5916 mmol/mol (7.51.4%)], body weight (77.8 +/- 13.9 vs 74.7 +/- 12.5 kg) and systolic blood pressure (133 +/- 18 vs 126 +/- 12 mmHg) in the study participants. Heart rate and QTc interval were not changed by sodium-glucose co-transporter-2 inhibitor treatment, but QTc dispersion was significantly reduced (median, 48.8 vs 44.2 ms). Sodium-glucose co-transporter-2 inhibitor treatment reversed QTc dispersion more in participants who had larger QTc dispersion before the treatment. Changes in systolic blood pressure (Spearman's = 0.319; P=0.031), but not in HbA(1c) concentration, were correlated with changes in QTc dispersion after sodium-glucose co-transporter-2 inhibitor treatment. ConclusionsThe findings suggest that sodium-glucose co-transporter-2 inhibitor treatment reverses ventricular repolarization heterogeneity in people with Type 2 diabetes, independently of its effect on glycaemic control. The favourable effect on ventricular repolarization heterogeneity could be the mechanism by which empaglifozin reduced cardiovascular events in a recent study.

DOI

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

Shingo Muratsubaki, Atsushi Kuno, Masaya Tanno, Takayuki Miki, Toshiyuki Yano, Hirohito Sugawara, Satoru Shibata, Koki Abe, Satoko Ishikawa, Kouhei Ohno, Yukishige Kimura, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Masashi Mizuno, Tetsuji Miura

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP )  7 ( 1 ) 5311  2017年07月  [査読有り]

　概要を見る

Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we hypothesized that suppression of autophagic response underlies aggravation of renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal artery in the contralateral kidney. Levels of serum creatinine and blood urea nitrogen and tubular injury score after I/R were significantly higher in OLETF than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic activation in response to I/R and significantly attenuated I/R-induced renal injury. Collectively, these findings indicate that suppressed autophagic activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.

DOI PubMed

循環器内科学 心不全の発症進展におけるAMPデアミナーゼの役割

舘越 勇輝, 丹野 雅也

医学のあゆみ ( 医歯薬出版(株) )  262 ( 3 ) 243 - 244  2017年07月

Suppression of autophagic flux contributes to cardiomyocyte death by activation of necroptotic pathways.

Ogasawara M, Yano T, Tanno M, Abe K, Ishikawa S, Miki T, Kuno A, Tobisawa T, Muratsubaki S, Ohno K, Tatekoshi Y, Nakata K, Ohwada W, Miura T

Journal of molecular and cellular cardiology   108   203 - 213  2017年07月  [査読有り]

DOI PubMed

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease.

Tobisawa T, Yano T, Tanno M, Miki T, Kuno A, Kimura Y, Ishikawa S, Kouzu H, Nishizawa K, Yoshida H, Miura T

Basic research in cardiology ( SPRINGER HEIDELBERG )  112 ( 3 ) 31  2017年05月  [査読有り]

　概要を見る

Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56.3 +/- 4.6 vs. 41.4 +/- 2.0%). In SNx group, myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3 beta was significantly suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by Ku-0063794 significantly increased infarct size in the Sham group but not in the SNx group. There was no difference between the two groups in activities of mTORC2 and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit B55 alpha, which specifically targets Akt-Thr308, was reduced by 24% in the SNx group. Knockdown of B55 alpha by siRNA increased baseline p-Akt-Thr308 and blunted Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293 cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55 alpha inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired Akt activation by insufficient Ser473 phosphorylation upon reperfusion contributes to infarct size enlargement by CKD.

DOI PubMed

2型糖尿病による腎虚血再灌流障害の増悪におけるautophagy障害の役割

菅原 浩仁, 茂庭 仁人, 柴田 智, 山下 智久, 村椿 真悟, 久野 篤史, 矢野 俊之, 丹野 雅也, 三木 隆幸, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 3 ) 226 - 226  2017年04月

多腺性自己免疫症候群3A型に房室ブロックを合併した一例 抗Ro/SS-A抗体との関連

中田 圭, 矢野 俊之, 大島 洸人, 古橋 眞人, 丹野 雅也, 斎藤 重幸, 三木 隆幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  60 ( Suppl.1 ) S - 452  2017年04月

Toll様受容体の活性化により2型糖尿病における心筋梗塞後のAKIに対する腎臓の感受性が増大する(Increased Renal Susceptibility to AKI after Myocardial Infarction in Type 2 Diabetes is Mediated by Augmented Activation of Toll-like Receptors)

大野 紘平, 久野 篤史, 三木 隆幸, 丹野 雅也, 矢野 俊之, 大和田 渉, 木村 幸滋, 安部 功記, 中田 圭, 舘越 勇輝, 三浦 哲嗣

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  81回   PJ - 594  2017年03月

多発性脳梗塞にて発症し、診断と治療効果の指標にPET-CTが有用であったLoeffler心内膜心筋炎の1例

大岩 修太郎, 茂庭 仁人, 能登 貴弘, 瀬野 結, 永野 伸卓, 神津 英至, 村中 敦子, 矢野 俊之, 丹野 雅也, 三浦 哲嗣

心臓 ( (公財)日本心臓財団 )  49 ( 3 ) 253 - 259  2017年03月

　概要を見る

症例は70歳代、男性。2012年近医で好酸球増多を認めたが精査は行われなかった。2015年7月に複視を契機に多発性脳梗塞と診断され、心原性脳塞栓症の疑いで当科紹介入院となった。血液検査にてCRP高値(6.76mg/dL)に加え好酸球数(6,615/μL)と、好酸球脱顆粒の指標である好酸球性カチオン性蛋白(41.7μg/L)の著明な上昇を認めた。右室心内膜下心筋生検にて有意な所見は認めなかったが、PET-CTにて左室心尖部心内膜に異常集積を認めたため、Loeffler心内膜心筋炎による左室内血栓からの多発性脳梗塞と考え、プレドニゾロンおよび抗凝固療法を開始した。その後速やかにCRPと好酸球数は正常化し、塞栓症の再発は認めず、慢性期のPET-CTでは左室心尖部心内膜下の異常集積は消失していた。本症例では炎症病変が左室心尖部であったため右室中隔から採取した心筋生検に異常を認めなかったものと考えられた。動脈塞栓症に好酸球増加症を合併した場合、Loeffler心内膜心筋炎を念頭に早期にPET-CTを含めた精査、治療介入を行うことが重要である。(著者抄録)

Distinct risk factors of atrial fibrillation in patients with and without coronary artery disease: A cross-sectional analysis of the BOREAS-CAG Registry data

Naoto Murakami, Masaya Tanno, Nobuaki Kokubu, Junichi Nishida, Nobutaka Nagano, Hirofumi Ohnishi, Hiroshi Akasaka, Takayuki Miki, Kazufumi Tsuchihashi, Tetsuji Miura

Open Heart ( BMJ Publishing Group )  4 ( 1 ) e000573  2017年  [査読有り]

　概要を見る

Objective: Although risk factors of atrial fibrillation (AF) in the general population have been characterised, their impacts on patients with specific diseases are unclear. Our aim was to determine whether risk factors of AF are different in patients with and those without coronary artery disease (CAD). Methods: We enrolled 1871 consecutive patients who underwent coronary angiography for evaluation of symptoms suggestive of CAD in the BOREAS-CAG Registry between August 2014 and January 2015. After exclusion of patients with valvular heart disease or a history of PCI/cardiac surgery, 1150 patients contributed to multivariate logistic regression analysis to identify risk factors of AF. We also retrieved data for 361 consecutive patients with CAD admitted to Sapporo Medical University Hospital between April 2013 and July 2014 and analysed data for 166 patients using the same inclusion and exclusion criteria as those in the BOREAS-CAG Registry. Results: Unexpectedly, CAD was independently associated with the absence of AF. The patients were then divided into a non-CAD group (n=576) and a CAD group (n=574) for further analysis. The brain natriuretic peptide level showed a strong association with AF regardless of the presence or absence of CAD. In the non-CAD group, lack of statin use was independently associated with AF, whereas high serum uric acid level was an independent explanatory variable of AF in the CAD group. The association of AF with uric acid was confirmed in a separate group of patients (n=166) enrolled in the CAD cohort in Sapporo Medical University Hospital. Conclusions: Major risk factors of AF are different in patients with CAD and those without CAD. Patients with CAD are more likely to develop AF when the serum uric acid level is high, whereas no statin administration predicts development of AF in patients without CAD.

DOI PubMed

Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease-Induced Enlargement of Myocardial Infarct Size.

Nishizawa K, Yano T, Tanno M, Miki T, Kuno A, Tobisawa T, Ogasawara M, Muratsubaki S, Ohno K, Ishikawa S, Miura T

Hypertension (Dallas, Tex. : 1979)   68 ( 3 ) 697 - 706  2016年09月  [査読有り]

DOI PubMed

糖尿病が腎虚血再灌流障害に及ぼす影響 オートファジーとの関連

村椿 真悟, 久野 篤史, 大野 紘平, 丹野 雅也, 矢野 俊之, 水野 雅司, 西沢 慶太郎, 大和田 渉, 舘越 勇輝, 中田 圭, 三木 隆幸, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  58 ( 3 ) 276 - 276  2016年05月

睡眠呼吸障害が血糖変動に与える影響の検討

中田 圭, 丹野 雅也, 矢野 俊之, 小笠原 淳, 赤坂 憲, 古橋 眞人, 三木 隆幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  59 ( Suppl.1 ) S - 191  2016年04月

RIP1によるp62の隔離はオートファジーの流れを障害し、心筋細胞におけるRIP1依存的ネクロトーシスにつながる(Sequestration of p62 by RIP1 Impairs Autophagic Flux and Leads to RIP1-dependent Necroptosis in Cardiomyocytes)

Ogasawara Makoto, Yano Toshiyuki, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Tobisawa Toshiyuki, Muratsubaki Shingo, Ono Kouhei, Nishizawa Keitaro, Ishikawa Satoko, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  80 ( Suppl.I ) 2404 - 2404  2016年03月

糖尿病心臓のAMP deaminaseの活性化においては翻訳後修飾ではなくfructose 1,6-diphosphateの枯渇が主要な役割を果たす(Depletion of Fructose 1,6-diphosphate but not Post-translational Modification Plays a Major Role in Activation of AMP Deaminase in Diabetic Hearts)

Tatekoshi Yuki, Kouzu Hidemichi, Tanno Masaya, Kuno Atsushi, Ishikawa Satoko, Yano Toshiyuki, Miki Takayuki, Ogasawara Makoto, Tobisawa Toshiyuki, Ono Kouhei, Muratsubaki Shingo, Nishizawa Keitaro, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  80 ( Suppl.I ) 1115 - 1115  2016年03月

2型糖尿病初期ではAMI誘発性急性腎障害に対する感受性がTLR介在性メカニズムによって増加する(Susceptibility to AMI-induced Acute Kidney Injury is Increased by a TLR-mediated Mechanism in the Early Stage of Type 2 Diabetes)

Ono Kouhei, Kuno Atsushi, Miki Takayuki, Tanno Masaya, Yano Toshiyuki, Kouzu Hidemichi, Ogasawara Makoto, Tobisawa Toshiyuki, Muratsubaki Shingo, Nishizawa Keitaro, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  80 ( Suppl.I ) 1352 - 1352  2016年03月

Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy

Toshiyuki Yano, Shinya Shimoshige, Takayuki Miki, Masaya Tanno, Atsushi Mochizuki, Takefumi Fujito, Satoshi Yuda, Atsuko Muranaka, Makoto Ogasawara, Akiyoshi Hashimoto, Kazufumi Tsuchihashi, Tetsuji Miura

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY ( ELSEVIER SCI LTD )  91   6 - 9  2016年02月  [査読有り]

　概要を見る

Background: Activity of mTOR complex 1 (mTORC1) has been shown to be up-regulated in animal models of heart failure. Here, we investigated the change and role of mTORC1 in human nonischemic dilated cardiomyopathy (NICM). Methods: Endomyocardial biopsy specimens were obtained from patients with NICM (n = 52) and from Brugada syndrome patients with normal LVEF as controls (n = 10). The specimens were stained for phospho-ribosomal protein S6 (p-RpsG) and phospho-p70S6K (p-p70S6K), and the area with p-RpsG signal was used as an index of mTORC1 activity. Using median mTORC1 activity, patients were divided into a high mTORC1 activity (H-mTOR) group and a low mTORC1 activity (L-mTOR) group. Results: The ratio of p-Rps6-positive area in biopsy samples was 10-fold larger in patients with NICM than in controls (2.0 +/- 22% vs. 0.2 +/- 0.2%, p < 0.01). p-p70S6K signal level was higher in the H-mTOR group than in the L-mTOR group. The proportion of patients with a family history of cardiomyopathy was higher and the proportion of patients on ACE inhibitors or angiotensin receptor blockers was lower in the H-mTOR group than in the L-mTOR group. The p-Rps6-positive area was correlated with extent of myocardial fibrosis (r = 0.46, p < 0.01). The cardiac event-free survival rate during a 5-year follow-up period tended to be lower in the H-mTOR group than in the L-mTOR group (52.9% vs. 81.6%, P = 0.10). Conclusion: Aberrant activation of mTORC1 in cardiomyocytes was associated with myocardial fibrosis and a trend for worse prognosis in patients with NICM, indicating that persistently activated mTORC1 contributes to progression of human heart failure. (C) 2015 Elsevier Ltd. All rights reserved.

DOI

Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats.

Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Ishikawa S, Tobisawa T, Ogasawara M, Nishizawa K, Miura T

Cardiovascular diabetology   14   103  2015年08月  [査読有り]

DOI PubMed

心筋梗塞による急性腎障害に対する2型糖尿病の影響と死亡率の関連

大野 紘平, 久野 篤史, 村椿 真悟, 村瀬 弘通, 丹野 雅也, 矢野 俊之, 神津 英至, 飛澤 利之, 小笠原 惇, 西澤 慶太郎, 石川 聡子, 田中 希尚, 三木 隆幸, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  57 ( 3 ) 569 - 569  2015年04月

早期2型糖尿病腎ではオートファジーが亢進している

村椿 真悟, 久野 篤史, 大野 紘平, 丹野 雅也, 矢野 俊之, 神津 英至, 田中 希尚, 飛澤 利之, 小笠原 惇, 西沢 慶太郎, 石川 聡子, 三木 隆幸, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  57 ( 3 ) 569 - 569  2015年04月

慢性腎不全の虚血/再灌流障害への感受性亢進において再灌流中のmTORC2活性化障害は中心的な役割を果たす(Impairment of mTORC2 Activation upon Reperfusion Plays a Pivotal Role in Increased Susceptibility to Ischemia/Reperfusion Injury in Chronic Renal Failure)

Tobisawa Toshiyuki, Yano Toshiyuki, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Ogasawara Makoto, Muratsubaki Shingo, Nishizawa Keutarou, Sugawara Hirohito, Ishikawa Satoko, Yoshida Hideaki, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  79 ( Suppl.I ) 2071 - 2071  2015年03月

Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart.

Kouzu H, Miki T, Tanno M, Kuno A, Yano T, Itoh T, Sato T, Sunaga D, Murase H, Tobisawa T, Ogasawara M, Ishikawa S, Miura T

Journal of molecular and cellular cardiology   80   136 - 145  2015年03月  [査読有り]

DOI PubMed

The effects of resveratrol and SIRT1 activation on dystrophic cardiomyopathy

Atsushi Kuno, Masaya Tanno, Yoshiyuki Horio

RESVERATROL AND HEALTH ( BLACKWELL SCIENCE PUBL )  1348   46 - 54  2015年  [査読有り]

　概要を見る

The muscular dystrophies, which cause progressive weakening of the skeletal muscles, are frequently associated with cardiomyopathy. In fact, the leading cause of mortality in patients with Duchenne muscular dystrophy, the most common and most severe type of muscular dystrophy, is heart failure due to cardiomyopathy. Therefore, more effective methods for treating cardiomyopathy are expected to improve long-term outcomes for patients with Duchenne muscular dystrophy. Our recent preclinical data show that treatment with the SIRT1 activator resveratrol is beneficial for dystrophic cardiomyopathy. We examined the effects of resveratrol treatment in two different models of muscular dystrophy: dystrophin-deficient mdx mice and delta-sarcoglycan-deficient TO-2 hamsters. In both models, resveratrol suppressed cardiac hypertrophy, preserved cardiac function, and reduced tissue fibrosis in the diseased heart. Importantly, resveratrol significantly improved survival in TO-2 hamsters. Resveratrol also attenuated skeletal muscle pathology in mdx mice. These promising results indicate resveratrol's potential for clinical translation to treat cardiomyopathy in patients with muscular dystrophies.

DOI

Translocation of Glycogen Synthase Kinase-3 beta (GSK-3 beta), a Trigger of Permeability Transition, Is Kinase Activity-dependent and Mediated by Interaction with Voltage-dependent Anion Channel 2 (VDAC2)

Tanno Masaya, Kuno Atsushi, Ishikawa Satoko, Miki Takayuki, Kouzu Hidemichi, Yano Toshiyuki, Murase Hiromichi, Tobisawa Toshiyuki, Ogasawara Makoto, Horio Yoshiyuki, Miura Tetsuji

JOURNAL OF BIOLOGICAL CHEMISTRY   289 ( 42 ) 29285 - 29296  2014年10月  [査読有り]

DOI

Does glycemic control reverse dispersion of ventricular repolarization in type 2 diabetes?

Takayuki Miki, Toshiyuki Tobisawa, Tatsuya Sato, Masaya Tanno, Toshiyuki Yano, Hiroshi Akasaka, Atsushi Kuno, Makoto Ogasawara, Hiromichi Murase, Shigeyuki Saitoh, Tetsuji Miura

CARDIOVASCULAR DIABETOLOGY ( BIOMED CENTRAL LTD )  13   125  2014年08月  [査読有り]

　概要を見る

Background: Abnormal ventricular repolarization is a predictor of cardiovascular mortality. In this study, we tested the hypothesis that glycemic control reverses abnormal ventricular repolarization in patients with type 2 diabetes. Methods: We analyzed longitudinal changes in repolarization indices of electrocardiograms in retrospectively enrolled 44 patients with type 2 diabetes and 44 age-matched healthy subjects. Results: In the diabetic group, BMI was greater, levels of HbA1c (10.0 +/- 1.6 vs. 5.6 +/- 0.3%) and triglyceride were higher and level of HDL cholesterol was lower than those in the control group. Although mean QTc intervals were similar (413.6 +/- 18.5 vs. 408.3 +/- 22.7 ms), QT dispersion (41.8 +/- 15.4 vs. 28.7 +/- 7.7 ms) and Tpeak-Tend in lead V5 (83.6 +/- 13.6 vs. 71.3 +/- 10.3 ms) were significantly longer in the diabetic group than in the control group, indicating increased heterogeneity of ventricular repolarization in type 2 diabetes. During follow-up of 36 patients in the diabetic group for 787 +/- 301 days, HbA1c level decreased to 7.3 +/- 1.6%, while BMI did not significantly change. In contrast to HbA1c, QT dispersion (45.8 +/- 15.0 ms) and Tpeak-Tend in lead V5 (83.6 +/- 10.6 ms) were not significantly reduced during the follow-up period. There was no correlation between the change in HbA1c and the change in QT dispersion or Tpeak-Tend. Conclusions: Increased heterogeneity of ventricular repolarization in type 2 diabetic patients was not reduced during the relatively short follow-up period despite significantly improved glycemic control.

DOI PubMed

Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2.

Sato T, Kobayashi T, Kuno A, Miki T, Tanno M, Kouzu H, Itoh T, Ishikawa S, Kojima T, Miura T, Tohse N

American journal of physiology. Heart and circulatory physiology   306 ( 7 ) H1054 - 65  2014年04月  [査読有り]

DOI PubMed

ミトコンドリアKATPチャンネル活性化による酸化ストレス後のmPTP再閉鎖促進は残存ROS産生の抑制により達成される(Acceleration of mPTP Re-closure after Oxidant Stress by Mitochondrial KATP Channel Activation is Achieved by Suppression of Residual ROS Production)

Ogasawara Makoto, Tanno Masaya, Kuno Atsushi, Ishikawa Satoko, Murase Hiromichi, Tobisawa Toshiyuki, Kouzu Hidemichi, Yano Toshiyuki, Miki Takayuki, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  78 ( Suppl.I ) 323 - 324  2014年03月

慢性腎不全は虚血/再灌流傷害に対する心筋感受性を高める(Chronic Renal Failure Enhances Myocardial Susceptibility to Ischemia/Reperfusion Injury)

Tobisawa Toshiyuki, Yano Toshiyuki, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Murase Hiromichi, Ogasawara Makoto, Ishikawa Satoko, Yoshida Hideaki, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  78 ( Suppl.I ) 269 - 269  2014年03月

糖尿病ラットにおいてIncretinを中心とする治療により心筋オートファジーフラックスが回復し、心筋梗塞後の死亡率が減少する(Incretin-based Therapy Restores Myocardial Autophagic Flux and Reduces Mortality after Myocardial Infarction in Diabetic Rats)

Murase Hiromichi, Kuno Atsushi, Miki Takayuki, Tanno Masaya, Yano Toshiyuki, Kouzu Hidemichi, Tobisawa Toshiyuki, Ogasawara Makoto, Ishikawa Satoko, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  78 ( Suppl.I ) 401 - 402  2014年03月

心保護シグナル伝達におけるmTORC2およびリボソーム蛋白質S6の中心的役割(The Pivotal Role of mTORC2 and Ribosomal Protein S6 in Cardioprotective Signaling)

Yano Toshiyuki, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Murase Hiromichi, Ogasawara Makoto, Tobisawa Toshiyuki, Ishikawa Satoko, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  78 ( Suppl.I ) 470 - 470  2014年03月

Accelerated recovery of mitochondrial membrane potential by GSK-3β inactivation affords cardiomyocytes protection from oxidant-induced necrosis.

Sunaga D, Tanno M, Kuno A, Ishikawa S, Ogasawara M, Yano T, Miki T, Miura T

PloS one   9 ( 11 ) e112529  2014年  [査読有り]

DOI PubMed

Titinによる心室スティフネスの変化は、2型糖尿病心臓における急性収縮期圧負荷により示された拡張機能障害を生じる可能性がある(Changes in Titin-based Ventricular Stiffness May Underlie Diastolic Dysfunction Unmasked by Acute Systolic Pressure Overloading in Type 2 Diabetic Hearts)

Kouzu Hidemichi, Kuno Atsushi, Miki Takayuki, Tanno Masaya, Itoh Takahito, Sato Tatsuya, Sunaga Daisuke, Murase Hiromichi, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  77 ( Suppl.I ) 64 - 64  2013年03月

虚血中のcyclophilin Dと無機リン酸担体の相互作用はmPTP開口の閾値と再灌流誘発性細胞壊死を決定する(Interaction of Cyclophilin D with Inorganic Phosphate Carrier during Ischemia Determines Threshold for mPTP Opening and Reperfusion-induced Cell Necrosis)

Itoh Takahito, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kouzu Hidemichi, Sato Tatsuya, Sunaga Daisuke, Murase Hiromichi, Ishikawa Satoko, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  77 ( Suppl.I ) 45 - 45  2013年03月

mPTP再閉鎖の促進はROS誘発性壊死を防ぐミトコンドリアKATPチャネルの活性化によって心筋細胞を防御する(Promotion of Re-closure of the mPTP Underlies Cardiomyocyte Protection by Activation of the Mitochondrial KATP Channel against ROS-induced Necrosis)

Sunaga Daisuke, Kuno Atsushi, Ishikawa Satoko, Miki Takayuki, Tanno Masaya, Kouzu Hidemichi, Itoh Takahito, Sato Tatsuya, Murase Hiromichi, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  77 ( Suppl.I ) 245 - 245  2013年03月

2型糖尿病の心筋におけるミトコンドリア蛋白脱アセチル化酵素SIRT3の役割(Role of SIRT3, a Mitochondrial Protein Deacetylase, in Type 2 Diabetic Myocardium)

Kuno Atsushi, Itoh Takahito, Sato Tatsuya, Kouzu Hidemichi, Tanno Masaya, Miki Takayuki, Horio Yoshiyuki, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  77 ( Suppl.I ) 168 - 168  2013年03月

VDAC2との相互作用はGSK3Bのミトコンドリア移行をキナーゼ活性依存性に促進し、細胞死を誘発する(Interaction with VDAC2 Promotes Mitochondrial Translocation of GSK3β in a Kinase Activity-Dependent Manner and Induces Cell Death)

Tanno Masaya, Sunaga Daisuke, Ishikawa Satoko, Itoh Takahito, Kouzu Hidemichi, Sato Tatsuya, Kuno Atsushi, Murase Hiromichi, Miki Takayuki, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  77 ( Suppl.I ) 55 - 56  2013年03月

Resveratrol improves cardiomyopathy in dystrophin-deficient mice through SIRT1 protein-mediated modulation of p300 protein.

Kuno A, Hori YS, Hosoda R, Tanno M, Miura T, Shimamoto K, Horio Y

The Journal of biological chemistry   288 ( 8 ) 5963 - 5972  2013年02月  [査読有り]

DOI PubMed

特発性右房拡張症の1例

菅原 浩仁, 小笠原 惇, 村中 敦子, 川向 美奈, 望月 敦史, 伊藤 孝仁, 丹野 雅也, 下重 晋也, 湯田 聡, 橋本 暁佳, 土橋 和文, 三浦 哲嗣

超音波医学 ( (公社)日本超音波医学会 )  40 ( 1 ) 33 - 33  2013年01月

Histopathology of the pancreas in fulminant type 1 diabetes after 23-year follow-up: a case report

Tatsuya Sato, Takayuki Miki, Naoto Murakami, Yoshihiko Hirohashi, Hidemichi Kouzu, Masato Furuhashi, Masaya Tanno, Satoshi Yuda, Shigeyuki Saitoh, Tadashi Hasegawa, Tetsuji Miura

PATHOLOGY INTERNATIONAL ( WILEY-BLACKWELL )  62 ( 12 ) 827 - 829  2012年12月  [査読有り]

DOI PubMed

Cytoprotective regulation of the mitochondrial permeability transition pore is impaired in type 2 diabetic Goto-Kakizaki rat hearts.

Itoh T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Murase H, Miura T

Journal of molecular and cellular cardiology   53 ( 6 ) 870 - 879  2012年12月  [査読有り]

DOI PubMed

軽度血圧上昇を伴う肥満2型糖尿病が左室・動脈カップリングに及ぼす影響

神津 英至, 須永 大介, 高田 明典, 久野 篤史, 丹野 雅也, 三木 隆幸, 三浦 哲嗣

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  35回   475 - 475  2012年09月

Emerging beneficial roles of sirtuins in heart failure.

Tanno M, Kuno A, Horio Y, Miura T

Basic research in cardiology   107 ( 4 ) 273  2012年07月  [査読有り]

DOI PubMed

Role of connexin-43 in protective PI3K-Akt-GSK-3β signaling in cardiomyocytes.

Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T, Sato T, Sunaga D, Murase H, Miura T

American journal of physiology. Heart and circulatory physiology   302 ( 12 ) H2536 - 44  2012年06月  [査読有り]

DOI PubMed

The mPTP and its regulatory proteins: final common targets of signalling pathways for protection against necrosis

Tetsuji Miura, Masaya Tanno

CARDIOVASCULAR RESEARCH ( OXFORD UNIV PRESS )  94 ( 2 ) 181 - 189  2012年05月  [査読有り]

　概要を見る

The mitochondrial permeability transition pore (mPTP) is a non-selective, large-conductance channel that is closed under physiological conditions. Opening of the mPTP, leading to abolition of mitochondrial functions, is a major mechanism of myocyte necrosis by ischaemia/reperfusion, and direct inhibition of mPTP opening by use of pharmacological or genetic manipulations limits infarct size in vivo. Multiple pro-survival signal pathways commonly target the mPTP and inhibit its opening. Although the molecular structure of the mPTP has not been established, recent studies have characterized roles of each mPTP subunit and functions of several proteins directly interacting with the mPTP. This article briefly describes the understanding of mPTP regulation and interaction of the mPTP with four proteins (hexokinase II, glycogen synthase kinase-3, signal transducer and activator of transcription 3, and sirtuin 3) that are downstream of signal pathways relevant to protection from ischaemia/reperfusion injury.

DOI PubMed

Ito電流は肥満2型糖尿病においてKv4.2およびKChIP2のダウンレギュレーションにより心内膜下で選択的に低下する(The Ito Current is Reduced Selectively in the Subendocardium by Downregulation of Kv4.2 and KChIP2 in Obese Type 2 Diabetes)

Sato Tatsuya, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kobayashi Takeshi, Kouzu Hidemichi, Itoh Takahito, Sunaga Daisuke, Murase Hiromichi, Ishikawa Satoko, Miura Tetsuji, Tohse Noritsugu

Circulation Journal ( (一社)日本循環器学会 )  76 ( Suppl.I ) 1592 - 1592  2012年03月

Ser9位のGSK-3βのリン酸化はミトコンドリアへの移行を阻害し、ミトコンドリアによる致死性ROS産生を減弱する(Phosphorylation of GSK-3β at Ser9 Inhibits Its Translocation to Mitochondria and Attenuates Lethal ROS Production by Mitochondria)

Tanno Masaya, Miki Takayuki, Kuno Atsushi, Kouzu Hidemichi, Itoh Takahito, Satoh Tatsuya, Ishikawa Satoko, Sunaga Daisuke

Circulation Journal ( (一社)日本循環器学会 )  76 ( Suppl.I ) 943 - 943  2012年03月

糖尿病の心臓において、無機リン酸輸送体のANTおよびシクロフィリンDとの相互作用増大がmPTP調節異常の根底にある(Increased Interaction of Inorganic Phosphate Carrier with ANT and Cyclophilin D Underlies Dysregulation of the mPTP in Diabetetic Hearts)

Itoh Takahito, Kouzu Hidemichi, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Satoh Tatsuya, Sunaga Daisuke, Murase Hiromichi, Ishikawa Satoko, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  76 ( Suppl.I ) 2171 - 2171  2012年03月

Role of ER stress in ventricular contractile dysfunction in type 2 diabetes.

Takada A, Miki T, Kuno A, Kouzu H, Sunaga D, Itoh T, Tanno M, Yano T, Sato T, Ishikawa S, Miura T

PloS one   7 ( 6 ) e39893  2012年  [査読有り]

DOI PubMed

Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy.

Hori YS, Kuno A, Hosoda R, Tanno M, Miura T, Shimamoto K, Horio Y

The Journal of pharmacology and experimental therapeutics   338 ( 3 ) 784 - 794  2011年09月  [査読有り]

DOI PubMed

軽度の心室機能不全とadrenalin刺激に対する反応鈍化は肥満2型糖尿病における心筋梗塞後の高い死亡率の素因となる(Slight Ventricular Dysfunction and Blunted Response to Adrenergic Stimulation Predispose to Higher Mortality after Infarction in Obese Type 2 Diabetes)

Takada Akifumi, Miki Takayuki, Tanno Masaya, Kuno Atsushi, Kohzu Hidemichi, Itoh Takahito, Satoh Tatsuya, Sunaga Daisuke, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  75 ( Suppl.I ) 44 - 44  2011年03月

2型糖尿病におけるerythropoietinに対する心筋反応欠如の根底にはミトコンドリア膜透過性遷移孔のERストレス介在性の異常調節がある(ER Stress-mediated Dysregulation of the Mitochondrial Permeability Transition Pore Underlies Loss of Myocardial Response to Erythropoietin in Type 2 Diabetes)

Kouzu Hidemichi, Miki Takayuki, Tanno Masaya, Yano Toshiyuki, Kuno Atsushi, Itoh Takahito, Sato Tatsuya, Takada Akifumi, Ishikawa Satoko, Miura Tetsuji

Circulation Journal ( (一社)日本循環器学会 )  75 ( Suppl.I ) 17 - 17  2011年03月

Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection.

Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K, Miura T

Hypertension (Dallas, Tex. : 1979)   57 ( 1 ) 110 - 115  2011年01月  [査読有り]

DOI PubMed

Erythropoietin (EPO) affords more potent cardioprotection by activation of distinct signaling to mitochondrial kinases compared with carbamylated EPO.

Sato T, Tanno M, Miki T, Yano T, Sato T, Shimamoto K, Miura T

Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy ( 5-6 )  24   401 - 408  2010年12月  [査読有り]

DOI PubMed

Roles of phospho-GSK-3β in myocardial protection afforded by activation of the mitochondrial K ATP channel.

Terashima Y, Sato T, Yano T, Maas O, Itoh T, Miki T, Tanno M, Kuno A, Shimamoto K, Miura T

Journal of molecular and cellular cardiology   49 ( 5 ) 762 - 770  2010年11月  [査読有り]

DOI PubMed

Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis

Tetsuji Miura, Masaya Tanno, Tatsuya Sato

CARDIOVASCULAR RESEARCH ( OXFORD UNIV PRESS )  88 ( 1 ) 7 - 15  2010年10月  [査読有り]

　概要を見る

Multiple cardioprotective signal pathways that are activated by ischaemic preconditioning (IPC) and those by IPC mimetics converge on mitochondria. Recent studies have shown that pools of Akt, protein kinase C-epsilon, extracellular-regulated kinases, glycogen synthase kinase-3 beta (GSK-3 beta), and hexokinases (HK) I and II, are localized in mitochondria in addition to their pools in the cytosol. Accumulating evidence indicates that such 'mitochondrial protein kinases' receive signals from cytosolic molecules and enhance tolerance of myocytes to injury. Proteomic analyses suggest that these kinases form complexes with each other and with subunit proteins of the mitochondrial permeability transition pore (mPTP). Functional relationships between the protein kinases in mitochondria have not been fully clarified, but GSK-3 beta and HKs appear to be at the end of the signal pathways and directly responsible for inhibition of opening of the mPTP and, thus, for myocyte protection from necrosis. In this review, recent findings supporting roles of mitochondrial protein kinases in protection from myocardial necrosis after ischaemia/reperfusion are summarized and discussed.

DOI PubMed

Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells

Toshiya Sugino, Mitsuhisa Maruyama, Masaya Tanno, Atsushi Kuno, Kiyohiro Houkin, Yoshiyuki Horio

FEBS LETTERS ( WILEY )  584 ( 13 ) 2821 - 2826  2010年07月  [査読有り]

　概要を見る

SIRT1, a NAD(+)-dependent protein deacetylase, is known to have neural functions. However, despite its cytoplasmic expression in some neural cells, its cytoplasmic function, if any, is unknown. Here we found that PC12 (pheochromocytoma) cells expressed SIRT1 in the cytoplasm. Nerve growth factor (NGF)-induced neurite outgrowth of these cells was promoted by activators of SIRT1, while inhibitors of SIRT1 or SIRT1-siRNA significantly inhibited it. The overexpression of a mutant SIRT1 that localised to the cytoplasm but not the nucleus enhanced the NGF-dependent neurite outgrowth, and a cytoplasmic dominant-negative SIRT1 suppressed it. Thus, cytoplasmic SIRT1 increases the NGF-induced neurite outgrowth of PC12 cells. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI

Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells.

Sugino T, Maruyama M, Tanno M, Kuno A, Houkin K, Horio Y

FEBS letters   584 ( 13 ) 2821 - 2826  2010年07月  [査読有り]

DOI PubMed

Mitochondria and GSK-3beta in cardioprotection against ischemia/reperfusion injury.

Miura T, Tanno M

Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy ( 3 )  24   255 - 263  2010年06月  [査読有り]

DOI PubMed

Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure.

Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, Shimamoto K, Horio Y

The Journal of biological chemistry   285 ( 11 ) 8375 - 8382  2010年03月  [査読有り]

DOI PubMed

Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts.

Hotta H, Miura T, Miki T, Togashi N, Maeda T, Kim SJ, Tanno M, Yano T, Kuno A, Itoh T, Satoh T, Terashima Y, Ishikawa S, Shimamoto K

Circulation research   106 ( 1 ) 129 - 132  2010年01月  [査読有り]

DOI PubMed

Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition.

Miki T, Miura T, Hotta H, Tanno M, Yano T, Sato T, Terashima Y, Takada A, Ishikawa S, Shimamoto K

Diabetes ( 12 )  58   2863 - 2872  2009年12月  [査読有り]

DOI PubMed

Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning.

Naitoh K, Yano T, Miura T, Itoh T, Miki T, Tanno M, Sato T, Hotta H, Terashima Y, Shimamoto K

American journal of physiology. Heart and circulatory physiology ( 2 )  296   H396 - 403  2009年02月  [査読有り]

DOI PubMed

Ser9 phosphorylation of mitochondrial GSK-3beta is a primary mechanism of cardiomyocyte protection by erythropoietin against oxidant-induced apoptosis.

Ohori K, Miura T, Tanno M, Miki T, Sato T, Ishikawa S, Horio Y, Shimamoto K

American journal of physiology. Heart and circulatory physiology ( 5 )  295   H2079 - 86  2008年11月  [査読有り]

DOI PubMed

Adenine nucleotide translocator, a mitochondrial carrier protein, and fate of cardiomyocytes after ischaemia/reperfusion

Masaya Tanno, Tetsuji Miura

CARDIOVASCULAR RESEARCH ( OXFORD UNIV PRESS )  80 ( 1 ) 1 - 2  2008年10月  [査読有り]

DOI PubMed

Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation

Shin Hisahara, Susumu Chiba, Hiroyuki Matsumoto, Masaya Tanno, Hideshi Yagi, Shun Shimohama, Makoto Sato, Yoshiyuki Horio

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA ( NATL ACAD SCIENCES )  105 ( 40 ) 15599 - 15604  2008年10月  [査読有り]

　概要を見る

Neural precursor cells (NPCs) differentiate into neurons, astrocytes, and oligodendrocytes in response to intrinsic and extrinsic changes. Notch signals maintain undifferentiated NPCs, but the mechanisms underlying the neuronal differentiation are largely unknown. We show that SIRT1, an NAD(+)-dependent histone deacetylase, modulates neuronal differentiation. SIRT1 was found in the cytoplasm of embryonic and adult NPCs and was transiently localized in the nucleus in response to differentiation stimulus. SIRT1 started to translocate into the nucleus within 10 min after the transfer of NPCs into differentiation conditions, stayed in the nucleus, and then gradually retranslocated to the cytoplasm after several hours. The number of neurospheres that generated Tuj1(+) neurons was significantly decreased by pharmacological inhibitors of SIRT1, dominant-negative SIRT1 and SIRT1-siRNA, whereas overexpression of SIRT1, but not that of cytoplasm-localized mutant SIRT1, enhanced neuronal differentiation and decreased Hes1 expression. Expression of SIRT1-siRNA impaired neuronal differentiation and migration of NPCs into the cortical plate in the embryonic brain. Nuclear receptor corepressor (N-CoR), which has been reported to bind SIRT1, promoted neuronal differentiation and synergistically increased the number of Tuj1(+) neurons with SIRT1, and both bound the Hes1 promoter region in differentiating NPCs. Hes1 transactivation by Notch1 was inhibited by SIRT1 and/or N-CoR. Our study indicated that SIRT1 is a player of repressing Notch1-Hes1 signaling pathway, and its transient translocation into the nucleus may have a role in the differentiation of NPCs.

DOI

Limitation of infarct size by erythropoietin is associated with translocation of Akt to the mitochondria after reperfusion.

Kobayashi H, Miura T, Ishida H, Miki T, Tanno M, Yano T, Sato T, Hotta H, Shimamoto K

Clinical and experimental pharmacology & physiology ( 7 )  35   812 - 819  2008年07月  [査読有り]

DOI PubMed

Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection.

Nishihara M, Miura T, Miki T, Tanno M, Yano T, Naitoh K, Ohori K, Hotta H, Terashima Y, Shimamoto K

Journal of molecular and cellular cardiology ( 5 )  43   564 - 570  2007年11月  [査読有り]

DOI PubMed

Delta-opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-epsilon-mediated phosphorylation of connexin 43.

Miura T, Yano T, Naitoh K, Nishihara M, Miki T, Tanno M, Shimamoto K

American journal of physiology. Heart and circulatory physiology ( 3 )  293   H1425 - 31  2007年09月  [査読有り]

DOI PubMed

Protecting ischemic hearts by modulation of SR calcium handling

Masaya Tanno, Tetsuji Miura

CARDIOVASCULAR RESEARCH ( ELSEVIER SCIENCE BV )  75 ( 3 ) 453 - 454  2007年08月  [査読有り]

DOI PubMed

Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1.

Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y

The Journal of biological chemistry ( 9 )  282   6823 - 6832  2007年03月  [査読有り]

DOI PubMed

Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway.

Miki T, Miura T, Tanno M, Nishihara M, Naitoh K, Sato T, Takahashi A, Shimamoto K

Basic research in cardiology ( 2 )  102   163 - 170  2007年03月  [査読有り]

DOI PubMed

Activation of ERK and suppression of calcineurin are interacting mechanisms of cardioprotection afforded by delta-opioid receptor activation.

Ikeda Y, Miura T, Sakamoto J, Miki T, Tanno M, Kobayashi H, Ohori K, Takahashi A, Shimamoto K

Basic research in cardiology ( 5 )  101   418 - 426  2006年09月  [査読有り]

DOI PubMed

Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3 beta.

Nishihara M, Miura T, Miki T, Sakamoto J, Tanno M, Kobayashi H, Ikeda Y, Ohori K, Takahashi A, Shimamoto K

American journal of physiology. Heart and circulatory physiology ( 2 )  291   H748 - 55  2006年08月  [査読有り]

DOI PubMed

Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling.

Miki T, Miura T, Yano T, Takahashi A, Sakamoto J, Tanno M, Kobayashi H, Ikeda Y, Nishihara M, Naitoh K, Ohori K, Shimamoto K

The Journal of pharmacology and experimental therapeutics ( 1 )  317   68 - 75  2006年04月  [査読有り]

DOI PubMed

Time window for the contribution of the delta-opioid receptor to cardioprotection by ischemic preconditioning in the rat heart

A Tsuchida, T Miura, M Tanno, Y Nozawa, H Kita, K Shimamoto

CARDIOVASCULAR DRUGS AND THERAPY ( SPRINGER )  12 ( 4 ) 365 - 373  1998年09月  [査読有り]

　概要を見る

The present study aimed to examine (1) whether the role of the opioid receptor in ischemic preconditioning (PC) is consistent regardless of the duration of ischemic insult and (2) which opioid receptor subtype contributes to PC. In the first series of experiments, the effects of PC, a nonselective opioid receptor antagonist (naloxone), and their combination on the infarct size after various durations of ischemia were assessed. In anesthetized, open-chest rats, the coronary artery was occluded for 20, 30, or 40 minutes to induce infarction and was reperfused for 3 hours, PC was performed with two cycles of 5-minute ischemia followed by 5-minute reperfusion before the sustained ischemia. At 25 minutes before the ischemia, naloxone was injected alone or in combination with subsequent PC. Infarct size was determined by tetrazolium staining and was expressed as a percentage of the risk area size (%IS/RA). In the second series of experiments, the effects of a delta-receptor selective antagonist, naltrindole (NTI), and a kappa-receptor selective antagonist, nor-binaltrophimine (nor-BNI), on PC before 30-minute coronary occlusion were assessed. In untreated controls, %IS/RA was 53.1 +/- 3.2 after 20 minutes, 67.9 +/- 3.9 after 30 minutes, and 87.8 +/- 2.0 after 40 minutes of ischemia, respectively. PC significantly reduced %IS/RA after 20, 30, and 40 minutes of ischemia to 3.1 +/- 0.8, 12.8 +/- 1.1, and 42.1 +/- 4.3, respectively (P < 0.05 vs, each control). Naloxone (6 mg/kg) partially attenuated the protection afforded by PC when the sustained ischemia was 30 minutes (%IS/RA = 27.4 +/- 4.5; P < 0.05 vs. PC), but this inhibitory effect of naloxone was not detected when the duration of the ischemia was 20 or 40 minutes. NTI (10 mg/kg) also attenuated infarct size limitation by PC after 30 minutes of ischemia (%IS/RA = 25.6 +/- 3.7), but nor-BNI (10 mg/kg) failed to modify infarct size limitation by PC (%IS/RA = 13.3 +/- 3.2). The present results suggest that activation of the opioid delta-receptor partly contributes to preconditioning against infarction in the rat and that there may be a time window (at around 30 minutes after the onset of ischemia) for this opioid receptor-mediated protective mechanism.