An attempt to regress cardiac hypertrophy by cardiomyocyte intracellular calmodulin control

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16K15443
• Research Institution: Yamaguchi University
• Principal Investigator: 矢野 雅文 山口大学, 大学院医学系研究科, 教授 (90294628)
• Co-Investigator(Kenkyū-buntansha): 山本 健 山口大学, 大学院医学系研究科, 教授 (50363122)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: EC coupling / 心肥大 / リアノジン受容体 / カルモジュリン

Outline of Annual Research Achievements

TACマウスのCaM, HDAC, 肥大遺伝子の解析:TAC手術後経時的に心筋細胞を単離培養しCaM, HDAC, GRK5が核、細胞質の分布の解析、リン酸化HDACの割合の解析、肥大遺伝子の発現の解析を行った。ACモデルでCaMの核へのtranslocationを認めた。
CaM HAマウスにおけるTAC後のCaM, HDAC, 肥大遺伝子の解析：我々はRyR2に対するCaMの結合を強める変異を見いだし、その変異RyR2を組み込んだノックイン(KI)マウス(CaM HAマウス)を作成した。CaM HAマウスでは、DPc10（CPVTにおけるRyR2内の変異部位：R2474Sを含んだペプチドで、native domainと分子間競合してドメインunzipを引き起こす）によりCaMが解離しない、すなわちドメイン連関障害→CaM解離が起きないことを確認している。このCaM HAマウスに対してTACを行い8週間後に心筋細胞を単離し、形態、予後、肥大遺伝子の発現を解析し、蛍光ラベルしたrecombinant CaM(F-CaM)を導入し、RyR2に対するCaMの親和性を計測する。これらの解析によりドメイン連関障害→CaM解離を抑制するという介入が心肥大を抑止することができるかを検討した。その結果CaMHAマウスにおいては、RyR2からのCaMの解離が抑制された結果、Ca leakが押さえられるばかりでなく、TAC後の心筋細胞の肥大が有意に抑制され、更に興味深いことに、心筋細胞の数も増えていることがわかった。

Research Products

• [Journal Article] Mutation-linked, excessively tight interaction between the calmodulin binding domain and the C-terminal domain of the cardiac ryanodine receptor as a novel cause of catecholaminergic polymorphic ventricular tachycardia (2018)
  • Author(s): Nishimura Shigehiko、Yamamoto Takeshi、Nakamura Yoshihide、Kohno Michiaki、Hamada Yoriomi、Sufu Yoko、Fukui Go、Nanno Takuma、Ishiguchi Hironori、Kato Takayoshi、Xu Xiaojuan、Ono Makoto、Oda Tetsuro、Okuda Shinichi、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Heart Rhythm Volume: in press Pages: in press
  • DOI: 10.1016/j.hrthm.2018.02.006
  • Peer Reviewed
• [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 Pages: 1250～1256
  • DOI: 10.1016/j.bbrc.2018.01.181
  • Peer Reviewed
• [Journal Article] Strict sequential catheter ablation strategy targeting the pulmonary veins and superior vena cava for persistent atrial fibrillation (2018)
  • Author(s): Yoshiga Yasuhiro、Shimizu Akihiko、Ueyama Takeshi、Ono Makoto、Fukuda Masakazu、Fumimoto Tomoko、Ishiguchi Hironori、Omuro Takuya、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Journal of Cardiology Volume: in press Pages: in press
  • DOI: 10.1016/j.jjcc.2018.01.004
  • Peer Reviewed
• [Journal Article] Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure (2017)
  • Author(s): Kato Takayoshi、Yamamoto Takeshi、Nakamura Yoshihide、et al.
  • Journal Title: Heart Rhythm Volume: 14 Pages: 120～127
  • DOI: 10.1016/j.hrthm.2016.10.019
  • Peer Reviewed
• [Journal Article] Urinary 8-Hydroxy-2'-Deoxyguanosine as a Myocardial Oxidative Stress Marker Is Associated With Ventricular Tachycardia in Patients With Active Cardiac Sarcoidosis (2017)
  • Author(s): Ishiguchi Hironori、Kobayashi Shigeki、Myoren Takeki、Kohno Michiaki、Nanno Takuma、Murakami Wakako、Oda Seiko、Oishi Keishi、Okuda Shinichi、Okada Munemasa、Suga Kazuyoshi、Yano Masafumi
  • Journal Title: Circulation: Cardiovascular Imaging Volume: 10 Pages: e006764～e006764
  • DOI: 10.1161/CIRCIMAGING.117.006764
  • Peer Reviewed
• [Journal Article] Serial changes in the side-branch ostial area after main-vessel stenting with kissing balloon inflation for coronary bifurcation lesions, assessed by 3D optical coherence tomography (2017)
  • Author(s): Fujimura Tatsuhiro、Okamura Takayuki、Tateishi Hiroki、Nakamura Takeshi、Yamada Jutaro、Oda Tetsuro、Mochizuki Mamoru、Nishimura Shigehiko、Nishimura Takashi、Yano Masafumi
  • Journal Title: European Heart Journal - Cardiovascular Imaging Volume: - Pages: -
  • DOI: 10.1093/ehjci/jex213
  • Peer Reviewed
• [Journal Article] Macroreentrant form of an adenosine 5'-triphosphate sensitive atrial tachycardia arising from the vicinity of the atrioventricular node involving the tricuspid and mitral annuli as its reentrant circuit (2017)
  • Author(s): Ueyama Takeshi、Shimizu Akihiko、Yoshiga Yasuhiro、Ono Makoto、Fumimoto Tomoko、Yano Masafumi
  • Journal Title: HeartRhythm Case Reports Volume: 3 Pages: 289～293
  • DOI: 10.1016/j.hrcr.2017.03.001
  • Peer Reviewed
• [Presentation] Stabilization of CaMKII-phosphorylated RyR2Prevents the Development of Age-related Car-diomyopathy Caused by Transgenic CaMKIIδc Overexpression (2018)
  • Author(s): Yoko Sufu, Shinichi Okuda, Yoko Okamoto, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Dantrolene Prevents Right Ventricular Hypertro-phy without Reducing Pulmonary Arterial Pres-sure in Monocrotaline-Induced PAH in Mice (2018)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Go Fukui, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Ryanodine Receptor Targeting Therapy InhibitsCardiomyocyte Hypertrophy and RelaxationImpairment in the Compensated Pressure-Overloaded Heart (2018)
  • Author(s): Michiaki Kono, Shigeki Kobayashi, Toshiro Kajii, Takuma Nanno, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Stabilization of Camkii-Phosphorylated Ryr2 by Dantrolene Prevents the Development of Age-Related Cardiomyopathy Caused by CamkiiδC Overexpression (2017)
  • Author(s): Yoko S Shimizu, Shinichi Okuda, Yoko Okamoto, Shigehiko Nishimura, Takayoshi Kato, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto and Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Channel Pore Mutation of RyR2 Cause Calcium Leak Independent of FKBP12.6-RyR2 and Calmodulin-RyR2 Affinity in R4496C/+ Knock-in Mouse (2017)
  • Author(s): Hitoshi Uchinoumi, Ivanita Stefanon, Yi Yang, Mena Said, Xiaoqiong Dong, Rogerio Faustino, Jose L Puglisi, Ye Chen-Izu, Razvan L Cornea, Xander H Wehrens, Wayne S Chen, Takeshi Yamamoto, Yano Masafumi and Donald M Bers
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Effect of Site Dependent RyR Stabilizers; a Clue to Trace a Signal Transmission Pathway Inside the RyR Molecule (2017)
  • Author(s): Go Fukui, Takeshi Yamamoto, Michiaki Kono, Yoshihide Nakamura, Takuma Nanno, Yoriomi Hamada, Yoko Sufu, Hironori Ishiguchi, Shigehiko Nishimura, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi and Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Dantrolene Prevents Right Ventricular Hypertrophy Without Reducing Pulmonary Arterial Pressure In Monocrotaline-induced PAH In Mice (2017)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Michiaki kono, Yoriomi Hamada, Go Fukui, Yoko Sufu, Takuma Nanno, Hironori Ishiguchi, Shigehiko Nishimura, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association