心筋細胞内カルモジュリン制御による心肥大退縮の試み

2016 Fiscal Year Research-status Report

• Project/Area Number: 16K15443
• Research Institution: Yamaguchi University
• Principal Investigator: 矢野 雅文 山口大学, 医学(系)研究科(研究院), 教授 (90294628)
• Co-Investigator(Kenkyū-buntansha): 山本 健 山口大学, 医学(系)研究科(研究院), 教授 (50363122)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: リアノジン受容体 / 心肥大

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。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

マウスの作成と実験がほぼ予定通りに進んでいる。

Strategy for Future Research Activity

CaM HAマウスに対するTAC後のCaM, HDAC, 肥大遺伝子の解析：
H28年度から継続してCaM, HDAC, 肥大遺伝子、形態、予後の解析を続ける。
GSH-CaM KIマウスに対するTAC後のCaM, HDAC, 肥大遺伝子の解析：
H28年度から継続してCaM, HDAC, 肥大遺伝子、形態、予後の解析を続ける。

Research Products

• [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 T, Yamamoto T, Nakamura Y, Nanno T, Fukui G, Sufu Y, Hamada Y, Maeda T, Nishimura S, Ishiguchi H, Murakami W, Fukuda M, Xu X, Hino A, Ono M, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M.
  • Journal Title: Heart Rhythm Volume: 14 Pages: 120-127
  • DOI: 10.1016/j.hrthm.2016.10.019.
  • Peer Reviewed / Open Access
• [Journal Article] Recombinant Atrial Natriuretic Peptide Prevents Aberrant Ca2+ Leakage through the Ryanodine Receptor by Suppressing Mitochondrial Reactive Oxygen Species Production Induced by Isoproterenol in Failing Cardiomyocytes. (2016)
  • Author(s): Murakami W, Kobayashi S, Susa T, Nanno T, Ishiguchi H, Myoren T, Nishimura S, Kato T, Hino A, Oda T, Okuda S, Yamamoto T, Yano M.
  • Journal Title: PLoS One Volume: 11 Pages: e0163250
  • DOI: 10.1371/journal.pone.0163250
  • Peer Reviewed / Open Access
• [Journal Article] An oxidative stress biomarker, urinary 8-hydroxy-2'-deoxyguanosine, predicts cardiovascular-related death after steroid therapy for patients with active cardiac sarcoidosis. (2016)
  • Author(s): Myoren T, Kobayashi S, Oda S, Nanno T, Ishiguchi H, Murakami W, Okuda S, Okada M, Takemura G, Suga K, Matsuzaki M, Yano M.
  • Journal Title: Int J Cardiol Volume: 212 Pages: 206-213
  • DOI: 10.1016/j.ijcard.2016.03.003
  • Peer Reviewed / Open Access
• [Presentation] Nuclear Translocation of Calmodulin, Which Dissociated From Cardiac Ryanodine Receptor, Promotes the Pathological Cardiac Hypertrophy (2016)
  • Author(s): Tetsuro Oda, Takeshi Yamamoto, Takayoshi Kato, Shigehiko Nishimura, Go Fukui, Shinichi Okuda, Shigeki Kobayashi, Donald Bers and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Improvement of Defective Channel Function on RyR2 Mediated by CaMKII Activation Suppresses Arrhythmogenesis in TnT-related Hypertrophic Cardiomyopathy (2016)
  • Author(s): Okuda, Yoko Sufu-Shimizu, Takayoshi Kato, Yoko Okamoto, Shigehiko Nishimura, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Correction of the Defective Channel Gating of Cardiac Ryanodine Receptor Improves Cardiac Function and Suppresses Ventricular Arrhythmia in Post Myocardial Infarction Heart Failure (2016)
  • Author(s): Hironori Ishiguchi, Shigeki Kobayashi, Michiaki Kohno, Takuma Nanno, Gou Fukui, Yoko Sufu-Shimizu, Yoriomi Hamada, Takako Maeda, Shigehiko Nishimura, Tetsuro Oda, Shinnichi Okuda, Takeshi Ueyama, Takeshi Yamamoto and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Correction of Impaired Calmodulin Binding to Ryr2 as a Novel Therapy of Lethal Arrhythmia in the Pressure-Overloaded Heart Failure (2016)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Takayoshi Kato, Yoriomi Hamada, Go Fukui, Yoko Sufu, Takuma Nanno, Shigehiko Nishimura, Hironori Ishiguchi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi and Masafumi Yano
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12 – 2016-11-15
  • Int'l Joint Research