研究者詳細 - 丹野　雅也

論文 - 丹野　雅也

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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]

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

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]

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]

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]

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]

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

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]

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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]

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]

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]

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

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論文 - 丹野　雅也