神津 英至

写真a

所属

医学部 循環器・腎臓・代謝内分泌内科学講座

職名

講師

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  • 札幌医科大学   循環器・腎臓・代謝内分泌内科学講座  

 

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  • 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

  • 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

  • Coexistence of sarcopenia and self‐reported weight loss is a powerful predictor of mortality in older patients with heart failure

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

    Geriatrics & Gerontology International ( Wiley )   2023年12月

     概要を見る

    Aim We examined whether the addition of self‐reported weight loss improves the accuracy of prediction of mortality caused by sarcopenia in heart failure (HF) patients. Methods We enrolled 477 HF patients (mean age 77 years) who received combined assessment of sarcopenia and self‐reported weight loss. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia. If the patients answered “yes” to the question “have you lost 2 kg or more in the past 6 months?”, they were diagnosed as having self‐reported weight loss. Results Sarcopenia and self‐reported weight loss coexisted in 32% of patients. During a median follow‐up period of 763 days, 65 patients (15%) died. Kaplan–Meier curves showed a significantly higher rate of mortality in HF patients with both sarcopenia and self‐reported weight loss than in HF patients with sarcopenia alone. Multivariate Cox proportional hazards analysis showed that the coexistence of sarcopenia and self‐reported weight loss is an independent predictor of mortality in HF patients. Inclusion of the coexistence of sarcopenia and self‐reported weight loss in the baseline model consisting of established prognostic markers significantly improved both the net reclassification index and the integrated discrimination index. Conclusions The coexistence of sarcopenia and self‐reported weight loss is a powerful predictor of mortality in HF patients. Geriatr Gerontol Int 2023; ••: ••–••.

    DOI

  • Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes.

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

    ESC heart failure    2023年12月  [国際誌]

     概要を見る

    AIMS: Iron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM. METHODS AND RESULTS: We enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of <10 points as individuals with SPPB scores of <10 points are most likely to be classified as frail and are at high risk for disability and future adverse events, including death. ID was defined as serum ferritin < 100 or 100-299 ng/mL when transferrin saturation (TSAT) was <20% according to the HF guidelines. Among the 562 HF patients (72 ± 14 years old; 56% male), 329 patients (58%) and 191 patients (34%) had ID and low physical function, respectively. Multivariate logistic regression analysis showed that TSAT as a continuous variable, but not ID, was a predictor of low physical function (odds ratio: 0.980, P = 0.024). Subgroup analysis showed that a significant association between low TSAT and low physical function was lost in HF patients with DM (P for interaction < 0.001). A spline dose-response curve for the relationship between TSAT and risk of low physical function with adjustments for covariates associated with low physical function in non-DM patients was almost linear with an increase in the risk of low physical function as the TSAT increased, but such a relationship was not found in the analyses of DM patients. A lack of close TSAT-SPPB relationship in HF patients with DM was confirmed also in a propensity-score-matched cohort. CONCLUSIONS: TSAT as a continuous variable, but not ID, was independently associated with physical function in HF patients, and a significant association was lost in patients with HF and DM, suggesting a limited impact of iron supplementation therapy in HF patients with DM.

    DOI PubMed

  • Independent Link Between Use of Mineralocorticoid Receptor Antagonists and Muscle Wasting in Heart Failure Patients Not Receiving Renin-Angiotensin System Inhibitors

    Ryo Numazawa, Satoshi Katano, Toshiyuki Yano, Ryohei Nagaoka, Katsuhiko Ohori, Hidemichi Kouzu, Suguru Honma, Yusuke Fujisawa, Kotaro Yamano, Arata Osanami, Masayuki Koyama, Akiyoshi Hashimoto, Masato Furuhashi

    Circulation Journal ( Japanese Circulation Society )   2023年10月

    DOI

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  • 脳梗塞発症を契機に診断されたLoffler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—A case of eosinophilic granulomatosis with polyangiitis complicated with Loffler's endocarditis diagnosed by the onset of cerebral infarction

    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   111 ( 8 ) 1580 - 1587  2022年08月

  • 糖尿病合併心不全における血漿分枝鎖アミノ酸の規定因子と予後予測能の検討

    神津英至, 片野唆敏, 大堀克彦, 大堀克彦, 長岡凌平, 沼澤瞭, 小山雅之, 小山雅之, 永野伸卓, 藤戸健史, 大和田渉, 佐藤達也, 矢野俊之

    糖尿病(Web)   65 ( Suppl )  2022年

    J-GLOBAL

  • 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   111 ( 8 )  2022年

    J-GLOBAL

  • 慢性心不全患者におけるShrunken Pore Syndromeと心血管イベントの関連性

    石郷 友之, 片野 唆敏, 矢野 俊之, 神津 英至, 大堀 克彦, 小山 雅之, 永野 伸卓, 藤戸 健史, 渡辺 絢子, 中野 敬太, 相神 智宏, 野々山 雅俊, 北川 学, 木明 智子, 藤居 賢, 戸田 貴大, 福士 将秀

    日本腎臓病薬物療法学会誌 ( 日本腎臓病薬物療法学会 )  10 ( 特別号 ) S152 - S152  2021年10月

    J-GLOBAL

  • プロトンポンプ阻害薬が心不全患者の骨格筋量に与える影響

    大堀 克彦, 矢野 俊之, 片野 唆敏, 長岡 凌平, 神津 英至, 永野 伸卓, 藤戸 健史, 西川 諒, 大和田 渉, 土橋 和文

    日本心臓病学会学術集会抄録 ( (一社)日本心臓病学会 )  69回   O - 104  2021年09月

    J-GLOBAL

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共同研究・競争的資金等の研究課題 【 表示 / 非表示

  • アミノ酸ー核酸代謝連関の制御による心不全の新規治療開発

    基盤研究(C)

    研究期間:

    2020年04月
    -
    2023年03月
     

    神津 英至, 久野 篤史, 矢野 俊之

     研究概要を見る

    ラット心筋におけるプロテオミクス解析において、AMPD3と分枝鎖アミノ酸(BCAA)の代謝律速酵素である分枝鎖α-ケト酸脱水素酵素(BCKDH)が直接結合していることを同定し、BCAA代謝の制御にAMPD3が関与していることが示唆された。さらに細胞分画実験において、この結合が細胞質及び小胞体分画で見られることを同定し、心筋においてBCAAがミトコンドリア外でも代謝されている可能性を見出した。新生ラット初代心筋細胞(NRCM)において、BCKDHサブユニットのノックダウンによって脂肪滴合成能障害がみられ、BCAA代謝が脂肪酸代謝に寄与してることを同定した。2型糖尿病モデルラット(OLETF)心筋において、BCAAの蓄積及びBCKDH-AMPD3結合比の低下がみられ、糖尿病心筋におけるBCAA代謝障害にAMPD3が関与している可能性が示唆された。さらに、OLETFの心筋メタボローム解析にて、SGLT2阻害薬によって最も増加傾向を示す代謝物がBCAAを始めとするアミノ酸であることを同定し、SGLT2阻害薬の心保護効果の機序としてアミノ酸代謝修飾の関与を同定した。 また、心不全症例において、血中アミノ酸プロファイリングが既存の危険因子と独立して予後を予測することを見出した。

  • 2型糖尿病による左室拡張機能障害の分子機序

    若手研究(B)

    研究期間:

    2013年04月
    -
    2015年03月
     

    神津 英至

     研究概要を見る

    2型糖尿病において、急性圧負荷が拡張期左室伸展性を低下させる機序を解析した。2型糖尿病心ではAMP deaminaseを介したアデニンヌクレオチドの分解が亢進しており急性圧負荷中に心筋ATP濃度が低下すること、心筋ATP濃度は左室等容弛緩時定数(tau)および左室拡張末期圧と負の相関を認めること、これらの左室拡張特性は間質の線維化や細胞骨格蛋白titinの変化が出現する前より認めることを明らかにした。