Evaluation of cardiac function for DCM and HCM knock-in model mouse during early postnatal development

• Project/Area Number: 16K08514
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: DU Cheng-Kun 国立研究開発法人国立循環器病研究センター, 研究所, 研究員 (90590646)
• Co-Investigator(Kenkyū-buntansha): 森本 幸生 国際医療福祉大学, 福岡保健医療学部, 教授 (50202362)
• Research Collaborator: Zhan Dong-Yun
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 心筋症 / モデル / 早期診断 / 心筋症モデル / 肥大型心筋症 / 早期治療 / 拡張型心筋症 / 心筋トロポニンT / ノックインマウス / 発症 / 突然死 / 心不全 / 循環器・高血圧 / 生理学 / シグナル伝達 / トランスレーショナルリサーチ

Outline of Final Research Achievements

HCM and DCM are often associated with severe heart failure and sudden death. Thus, early diagnosis and treatment is paramount for the reduction of its high mortality rate. The chief impetus of this study is to characterize the pathophysiology of knock-in mouse models of HCM and DCM. We showed that the S179F HCM mice developed left ventricular lumen narrowing and LV diastolic dysfunction before cardiac hypertrophy occured. The ΔK210 DCM mouse model developed LV systolic dysfunction and marked cardiac enlargement before LV wall became thinner. Further, ghrelin treatment (150 µg/kg/d s.c.) from fetal period has a benefit for attenuating cardiac remodeling and systolic dysfunction in the DCM mouse. Phenotypic changes in both mouse models occur at very early postnatal stage before weaning in the HCM and DCM mouse models. This suggests that these models are useful for the exploration of pathogenic mechanisms and therapeutics for very early onset HCM and DCM.

Academic Significance and Societal Importance of the Research Achievements

心筋症では、心筋トロポニンT（cTnT）などのサルコメア蛋白質において、様々な遺伝子変異が原因として同定されている。しかしながら、ヒト心筋症患者の病態を良く再現した動物モデルはこれまで殆どなかったため有効な治療法の開発が遅れている。我々は、マウスの内在性cTnT の特定部位にヒトDCMを発症させる変異ΔK210とHCMを発症させる変異S179Fを導入した二つのKI モデルの作製に成功した。本研究ではそれぞれの心筋症発症初期の病態形成に関する重要な知見が得られた。今後の若年突然死をはじめとする重要課題に対する理解や、心筋症の病態生理学に対して大きく貢献するものと考えられる。

Research Products

• [Journal Article] Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease. (2018)
  • Author(s): Katare R, Pearson JT, Lew JK, Wei M, Tsuchimouchi H, Du CK, Zhan DY, Umetani K, Shirai M, Schwenke DO
  • Journal Title: Front Physiol. Volume: 9 Pages: 696-696
  • DOI: 10.3389/fphys.2018.00696
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Overexpression of heart-specific small subunit of myosin light chain phosphatase results in heart failure and conduction disturbance (2018)
  • Author(s): Arimura Takuro、Muchir Antoine、Kuwahara Masayoshi、Morimoto Sachio、Ishikawa Taisuke、Du Cheng-Kun、Zhan Dong-Yun、Nakao Shu、Machida Noboru、Tanaka Ryo、Yamane Yoshihisa、Hayashi Takeharu、Kimura Akinori
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology Volume: epub Issue: 6 Pages: H1192-H1202
  • DOI: 10.1152/ajpheart.00696.2017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca 2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy (2018)
  • Author(s): Okuda Shinichi、Sufu-Shimizu Yoko、Kato Takayoshi、Fukuda Masakazu、Nishimura Shigehiko、Oda Tetsuro、Kobayashi Shigeki、Yamamoto Takeshi、Morimoto Sachio、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 496 Issue: 4 Pages: 1250-1256
  • DOI: 10.1016/j.bbrc.2018.01.181
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cardiotonic actions of quercetin and its metabolite tamarixetin through a digitalis-like enhancement of Ca 2+ transients (2018)
  • Author(s): Hayamizu Kengo、Morimoto Sachio、Nonaka Miki、Hoka Sumio、Sasaguri Toshiyuki
  • Journal Title: Archives of Biochemistry and Biophysics Volume: 637 Pages: 40-47
  • DOI: 10.1016/j.abb.2017.11.009
  • Peer Reviewed / Open Access
• [Journal Article] Targeted Genome Replacement via Homology-directed Repair in Non-dividing Cardiomyocytes (2017)
  • Author(s): Ishizu T, Higo S, Masumura Y, Kohama Y, Shiba M, Higo T, Shibamoto M, Nakagawa A, Morimoto S, Takashima S, Hikoso S, Sakata Y.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 9363-9363
  • DOI: 10.1038/s41598-017-09716-x
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac vagal control in a knock-in mouse model of dilated cardiomyopathy with a troponin mutation. (2017)
  • Author(s): Zhan DY, Du CK, Akiyama T, Morimoto S, Shimizu S, Kawada T, Shirai M, Pearson JT.
  • Journal Title: Auton Neurosci. Volume: 205 Pages: 33-40
  • DOI: 10.1016/j.autneu.2017.03.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 12,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through activation of GSK-3 (2017)
  • Author(s): Ai Fujita, Fumi Takahashi-Yanaga, Sachio Morimoto, Tatsuya Yoshihara, Masaki Arioka, Kazunobu Igawa, Katsuhiko Tomooka, Sumio Hoka, Toshiyuki Sasaguri
  • Journal Title: Hypertension Research Volume: 40 Issue: 2 Pages: 130-139
  • DOI: 10.1038/hr.2016.122
  • Peer Reviewed
• [Journal Article] Myocardial interstitial levels of serotonin and its major metabolite 5-hydroxyindole acetic acid during ischemia-reperfusion. (2017)
  • Author(s): Du CK, Zhan DY, Akiyama T, Inagaki T, Shishido T, Shirai M, Pearson JT.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 312(1) Issue: 1 Pages: H60-H67
  • DOI: 10.1152/ajpheart.00471.2016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Benefits of cardiac microdialysis technique in the cardiovascular research (2017)
  • Author(s): 秋山 剛, 清水 秀二, 杜 成坤, 戦 冬雲, 稲垣 董克, 吉本 光佐, 曽野部 崇, 川田 徹, ピアソン ジェームズ.
  • Journal Title: CIRCULATION CONTROL Volume: 38 Issue: 3 Pages: 208-217
  • DOI: 10.11312/ccm.38.208
  • NAID: 130006287937
  • ISSN: 0389-1844
  • Peer Reviewed
• [Journal Article] Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy. (2016)
  • Author(s): Ito K, Hongo K, Date T, Ikegami M, Hano H, Owada M, Morimoto S, Kashiwagi Y, Katoh D, Yoshino T, Yoshii A, Kimura H, Nagoshi T, Kajimura I, Kusakari Y, Akaike T, Minamisawa S, Ogawa K, Minai K, Ogawa T, Kawai M, Yajima J, Matsuo S, Yamane T, Taniguchi I, Morimoto S, Yoshimura M.
  • Journal Title: Int J Cardiol. Volume: 228 Pages: 821-827
  • DOI: 10.1016/j.ijcard.2016.11.176
  • Peer Reviewed / Open Access
• [Journal Article] 遺伝性拡張型心筋症に対する新規治療法の開発に向けて (2016)
  • Author(s): 戦 冬雲、杜 成坤、森本 幸生、秋山 剛、Daryl O. Schwenke、細田 洋司、寒川 賢治、白井 幹康、Pearson James
  • Journal Title: BIO Clinica Volume: 31 Pages: 101-104
• [Journal Article] GSK3β heterozygous knockout is cardioprotective in a knock-in mouse model of familial dilated cardiomyopathy (2016)
  • Author(s): Rasha Mohamed · Sachio Morimoto · Islam Ibrahim · Dong-Yun Zhan · Cheng-Kun Du · Masaki Arioka · Tatsuya Yoshihara · Fumi Takahashi-Yanaga · Toshiyuki Sasaguri
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: in press Issue: 11 Pages: H1808-H1815
  • DOI: 10.1152/ajpheart.00771.2015
  • Peer Reviewed
• [Journal Article] Monoamine oxidase-induced hydroxyl radical production and cardiomyocyte injury during myocardial ischemia-reperfusion in rats (2016)
  • Author(s): Tadakatsu Inagaki, Tsuyoshi Akiyama, Cheng-Kun Du, Dong-Yun Zhan, Misa Yoshimoto & Mikiyasu Shirai
  • Journal Title: Free Radical Research Volume: 50 Issue: 6 Pages: 645-653
  • DOI: 10.3109/10715762.2016.1162300
  • Peer Reviewed
• [Presentation] ヒト拡張型心筋症ノックインマウスモデルの出生後早期における心機能評価. (2018)
  • Author(s): 杜 成坤、戦 冬雲、森本 幸生、秋山 剛、白井 幹康、Pearson James.
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] Effects of Novel RyR2 Inhibitors on Diseased Hearts. (2018)
  • Author(s): Nagomi Kurebayashi, Takashi Murayama, Mai Tamura, Shuichi Mori, Mari Yuasa-Ishigami, Hiroyuki Kagechika, Junji Suzuki, Kazunori Kanemaru, MasamitsuIino, SachioMorimoto, TakashiSakurai.
  • Organizer: 63rd Annual Meeting of the Biophysical Society
  • Int'l Joint Research
• [Presentation] The Effects of Frequency of Voluntary Exercise on Cardiac Function in Dilated Cardiomyopathy Model Mice (2018)
  • Author(s): Masami Sugihara, Ryo Kakigi, Takashi Murayama, Takashi Miida, Takashi Sakurai, Sachio Morimoto, Nagomi Kurebayashi.
  • Organizer: 63rd Annual Meeting of the Biophysical Society
  • Int'l Joint Research
• [Presentation] Beneficial effects of donepezil in a knock-in mouse model of dilated cardiomyopathy caused by troponin T mutation (2017)
  • Author(s): Cheng-Kun Du, Dong-Yun Zhan, Sachio Morimoto, Tsuyoshi Akiyama, Mikiyasu Shirai, James T Pearson
  • Organizer: The 94th Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Hamamatsu
  • Year and Date: 2017-03-28
• [Presentation] Abnormalities of cardiac norepinephrine kinetics in a knock-in mouse model of dilated cardiomyopathy (2017)
  • Author(s): Dong-Yun Zhan, Cheng-Kun Du, Tsuyoshi Akiyama, Sachio Morimoto, Mikiyasu Shirai, James T Pearson
  • Organizer: The 94th Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Hamamatsu
  • Year and Date: 2017-03-28
• [Presentation] Effects of Alzheimer drug Aricept in a knock-in mouse model of dilated cardiomyopathy (2017)
  • Author(s): Cheng-Kun Du, Dong-Yun Zhan, Sachio Morimoto, Tsuyoshi Akiyama, Mikiyasu Shirai, James T Pearson
  • Organizer: The 90th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: Nagasaki
  • Year and Date: 2017-03-15
• [Presentation] Abnormal respiration and metabolism in the HCM knock-in model mouse. (2017)
  • Author(s): Du Cheng-Kun, Zhan Dong-Yun, Morimoto Sachio, Shirai Mikiyasu, Pearson James.
  • Organizer: The 95th Annual Meeting of the Physiological Society of Japan
• [Presentation] Carrier-mediated serotonin efflux from platelets in the heart. (2017)
  • Author(s): Sonobe Takashi, Akiyama Tsuyoshi, Du Chengkun, Pearson T James.
  • Organizer: The 95th Annual Meeting of the Physiological Society of Japan
• [Presentation] Cardiac vagal control in knock-in mouse model of dilated cardiomyopathy (2016)
  • Author(s): Dong-Yun Zhan, Cheng-Kun Du, Tsuyoshi Akiyama, Sachio Morimoto, Shuji Shimizu, Toru Kawada, Mikiyasu Shirai, James T Pearson
  • Organizer: The American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Book] 心不全（第2版）上卷ー最新の基礎・臨床研究の進歩ー 心筋ミオフィラメントCa感受性. (2018)
  • Author(s): 杜 成坤, 森本 幸生
  • Total Pages: 7
  • Publisher: 日本臨牀社