Pathogenic mechanism of congestive heart failure in a mouse model of dilated cardiomyopathy with brain serotonin dysfunction

• Project/Area Number: 23300145
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurophysiology and muscle physiology
• Research Institution: Kyushu University
• Principal Investigator: MORIMOTO Sachio 九州大学, 医学(系)研究科(研究院), 准教授 (50202362)
• Co-Investigator(Renkei-kenkyūsha): KATAFUCHI Toshihiko 九州大学, 大学院・医学研究院, 准教授 (80177401) ; TAKE Sachiko 九州大学, 大学院・医学研究院, 助教 (80253425) ; KUREBAYASHI Nagomi 順天堂大学, 医学部, 准教授 (50133335)
• Project Period (FY): 2011-11-18 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: うっ血性心不全 / うつ病 / 不安障害 / 脳 / セロトニン / トリプトファン / 遺伝的要因 / 拡張型心筋症 / 心不全 / 抗うつ薬 / 抗不安薬 / ノックインマウス / 迷走神経

Research Abstract

In this study, we explored the role of brain serotonin function in the development of congestive heart failure (HF), using knock-in mice bearing a sarcomeric protein mutation that causes dilated cardiomyopathy (DCM) on different genetic backgrounds; BALB/c and C57Bl/6. BALB/c background mice, which have brain serotonin dysfunction due to a single nucleotide polymorphism in tryptophan hydroxylase 2, developed congestive HF before died. In contrast, C57Bl/6 background mice with normal brain serotonin function developed no overt HF symptoms and died suddenly. Brain serotonin dysfunction plays a critical role in depression and anxiety and BALB/c mice exhibit depression- and anxiety-related behaviors. Drugs that could improve the brain serotonin function improved symptoms of severe congestive HF in DCM mice on the BALB/c background. These results strongly suggest that congenital or acquired brain serotonin dysfunction may play an important role in the development of congestive HF in DCM.

Research Products

• [Journal Article] Usefulness of running wheel for detection of congestive heart failure in dilated cardiomyopathy mouse model (2014)
  • Author(s): Sugihara M, Odagiri F, Suzuki T, Murayama T, Nakazato Y, Unuma K, Yoshida K, Daida H, Sakurai T, Morimoto S, Kurebayashi N.
  • Journal Title: PLoS One Volume: 8(1) Issue: 1 Pages: e55514-e55514
  • DOI: 10.1371/journal.pone.0055514
  • Peer Reviewed
• [Journal Article] Inherited cardiomyopathies caused by troponin mutations (2013)
  • Author(s): Lu Q-W, Wu X-Y, Morimoto S
  • Journal Title: J Geriatr Cardiol Volume: 10 Pages: 91-101
• [Journal Article] Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210 (2013)
  • Author(s): Inoue T, Kobirumaki-Shimozawa F, Kagemoto T, Fujii T, Terui T, Kusakari Y, Hongo K, Morimoto S, Ohtsuki I, Hashimoto K, Fukuda N
  • Journal Title: J Mol Cell Cardiol Volume: 63 Pages: 69-78
• [Journal Article] Familial dilated cardiomyopathy mutations uncouple Troponin I phosphorylation from changes in myofibrillar Ca^<2+>-sensitivity (2013)
  • Author(s): Memo M, Leung MC, Ward DG, Dos Remedios C, Morimoto S, Zhang L, Ravenscroft G, McNamara E, Nowak KJ, Marston SB, Messer AE
  • Journal Title: Cardiovasc Res Volume: 99 Issue: 1 Pages: 65-73
  • DOI: 10.1093/cvr/cvt071
  • Peer Reviewed
• [Journal Article] Depressed Frank–Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210 (2013)
  • Author(s): Takahiro Inoue, Fuyu Kobirumaki-Shimozawa, Tatsuya Kagemoto, Teruyuki Fujii, Takako Terui, Yoichiro Kusakari, Kenichi Hongo, Sachio Morimoto, Iwao Ohtsuki, Kazuhiro Hashimoto, Norio Fukuda
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 63 Pages: 69-78
  • Peer Reviewed
• [Journal Article] Inherited cardiomyopathies caused by troponin mutations (2013)
  • Author(s): Lu Q-W, Wu X-Y, Morimoto S
  • Journal Title: Journal of Geriatric Cardiology Volume: 10 Pages: 91-101
  • Peer Reviewed
• [Journal Article] Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure (2012)
  • Author(s): Li L, Morimoto S, Take S, Zhan D.-Y, Du C.-K, Wang Y.-Y, Fan X.-L, Yoshihara T, Takahashi-Yanaga F, Katafuchi T, Sasaguri T
  • Journal Title: J Mol Cell Cardiol Volume: 53 Issue: 6 Pages: 760-767
  • DOI: 10.1016/j.yjmcc.2012.08.006
  • Peer Reviewed
• [Journal Article] Multistep ion channel remodeling and lethal arrhythmia precede heart failure in a mouse model of inherited dilated cardiomyopathy (2012)
  • Author(s): Suzuki T, Shioya T, Murayama T,Sugihara M, Odagiri F, Nakazato Y, Nishizawa H, Chugun A, Sakurai T, Daida H, Morimoto S, Kurebayashi N
  • Journal Title: PLoS ONE Volume: 7(4)
• [Journal Article] Celecoxib and 2, 5-dimethyl-celecoxib prevent cardiac remodeling inhibitiAkt-mediated signal transduction in an inherited DCM mouse model (2011)
  • Author(s): Fan, X., Takahashi-Yanaga, F., Morimoto, S., Zhan, D.-Y., Igawa, K., Tomooka, K., & Sasaguri, T
  • Journal Title: Exp. Ther Volume: 338(1) Issue: 1 Pages: 2-11
  • DOI: 10.1124/jpet.111.179325
  • Peer Reviewed
• [Presentation] Effect of pimobendan on heart failure at different stages in a mouse model of inherited cardiomyopathy (2014)
  • Author(s): 野中 美希、森本 幸生、早水 憲吾、笹栗 俊之
  • Organizer: 日本薬理学会年会
  • Place of Presentation: 仙台
• [Presentation] Effect of pimobendan on heart failure in a mouse model inherited cardiomyopathy (2014)
  • Author(s): Nonaka M, Hayamizu K, Morimoto S
  • Organizer: Biophysical Society 58th Annual Meeting
  • Place of Presentation: San Francisco
• [Presentation] 遺伝性拡張型心筋症マウスを用いたピモベンダンの心不全治療効果の検討 (2013)
  • Author(s): 野中 美希、森本 幸生、早水 憲吾、笹栗 俊之
  • Organizer: 日本薬理学会西南部会
  • Place of Presentation: 福岡
• [Presentation] Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure (2013)
  • Author(s): 森本幸生
  • Organizer: 第86回 日本薬理学会年会
  • Place of Presentation: 福岡
• [Presentation] Comparison of disease phenolypes in mouse models of inherited cardiomyopathy on C57B.1/6 and BALB/c backgrounds (2012)
  • Author(s): Li, et al
  • Organizer: 日本薬理学会年会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-03-16
• [Presentation] Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure (2012)
  • Author(s): 森本幸生
  • Organizer: 第29回 国際心臓研究学会（ISHR）日本部会総会
  • Place of Presentation: 福岡
• [Presentation] 拡張型心筋症モデルマウスの心不全発症における脳内セロトニンレベルの役割(口演)
  • Author(s): 李 蕾, 森本 幸生, 戦 冬雲, 王 媛媛, 杜 成坤, 範 雪麗, 笹栗 俊之
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] C57B.l/6 とBALB/c 背景の遺伝性拡張型心筋症モデルマウス疾患表現型の比較(口演)
  • Author(s): 李 蕾, 森本 幸生, 戦 冬雲, 杜 成坤, 王 媛媛, 範 雪麗, 吉原 達也, 高橋 富美, 笹栗 俊之
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
• [Presentation] Role of Brain Serotonin Dysfunction in the Pathophysiology of Congestive Heart Failure (poster)
  • Author(s): Li L, Nonaka M, Morimoto S
  • Organizer: 第29回国際心臓研究学会(ISHR)日本部会
  • Place of Presentation: 福岡
• [Presentation] うっ血性心不全の病態生理学における脳セロとニン機能障害の役割(口演)
  • Author(s): 李蕾, 森本幸生, 武幸子, 戦冬雲, 杜成坤, 王媛媛, 範雪麗, 吉原達也, 高橋富美, 片渕俊彦, 笹栗俊之
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
• [Book] 論文ができてしまう!疾患モデルマウス表現型解析指南 (2011)
  • Author(s): 森本幸生
  • Total Pages: 477
  • Publisher: 中山書店
• [Remarks]
  • URL: http://www.med.kyushu-u.ac.jp/clipharm/
• [Remarks] 九州大学大学院医学研究院臨床薬理学分野
  • URL: http://www.med.kyushu-u.ac.jp/clipharm/index.html
• [Remarks] 九州大学研究者情報
  • URL: http://hyoka.ofc.kyushu-u.ac.jp/search/details/K000903/index.html
• [Remarks]
  • URL: http://www.med.kyushu-u.ac.jp/clipharm/index.html