細胞内Ca2+制御による新たな肥大型心筋症の分子標的療法の開発

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26670404
• 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): 奥田 真一 山口大学, 医学部附属病院, 助教 (90530212)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: カルシウムハンドリング / 肥大型心筋症 / リアノジン受容体

Outline of Annual Research Achievements

肥大型心筋症(HCM)は、著明な心筋肥大とともに致死的不整脈および心不全を生じるが、現時点で心肥大を退縮させる有効な薬物療法は存在しない。心肥大を生じる機序として、心筋細胞内Ca2+濃度との関連が報告されており、本研究ではHCM型トロポニンTトランスジェニックマウスおよび大動脈縮窄モデルを用いて、1)リアノジン受容体(RyR2)からのCa2+漏出による拡張期のCa2+濃度上昇と心肥大を来たす機序との関連性、2)Ca2+漏出の抑制による心筋筋小胞体機能の改善により拡張期の心筋細胞内Ca2+濃度上昇を防ぐことで、心肥大の退縮を起こしうるかを検討した。その結果、RyR2機能異常と心肥大との関連性の機序としてカルモジュリン依存性リン酸化キナーゼの活性化が関与していること、RyR2安定化によるCa2+漏出の抑制により心肥大～心不全への進行抑制が見られた。これらの結果から拡張期の心筋細胞内Ca2+濃度上昇抑制が心肥大退縮に対する治療戦略となりうる可能性が示唆された。

Research Products

• [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: 17 Pages: 206-213
  • DOI: 10.1016/j.ijcard.2016.03.003
  • Peer Reviewed
• [Journal Article] A low-dose β1-blocker in combination with milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum. (2015)
  • Author(s): Kobayashi S, Susa T, Ishiguchi H, Myoren T, Murakami W, Kato T, Fukuda M, Hino A, Suetomi T, Ono M, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Okuda S, Doi M, Yamamoto T, Yano M.
  • Journal Title: PLoS One Volume: 10 Pages: e0114314
  • DOI: 10.1371/journal.pone.0114314
  • Peer Reviewed / Open Access
• [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker of inflammatory activity in patients with cardiac sarcoidosis. (2015)
  • Author(s): Kobayashi S, Myoren T, Oda S, Inari M, Ishiguchi H, Murakami W, Fukuda M, Tanaka T, Okuda S, Nao T, Doi M, Yamada J, Okamura T, Hoshii Y, Suga K, Matsuzaki M, Yano M.
  • Journal Title: Int J Cardiol Volume: 190 Pages: 319-328
  • DOI: 10.1016/j.ijcard.2015.04.144
  • Peer Reviewed
• [Presentation] Inhibition of aberrant Ca2+ release through RyR2 mediated by CaMKII and Ca2+ buffering suppresses arrhythmogenesis in troponin T-related hypertrophic cardiomyopathy (2016)
  • Author(s): Okuda S, Kato T, Sufu Y, Fukuda M, Nichimura S, Kobayashi S, Oda T, Yamamoto T, Yano M
  • Organizer: Japanese Society of Cardiology
  • Place of Presentation: 宮城県仙台市 せんだい青葉山交流会場 特設会場
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] High Affinity CaM, but Not Normal Affinity CaM Can Prevent Arrhythmias in CPVT Which Mutation is Located at CaM-like Domain of RyR2. (2015)
  • Author(s): Nishimura S, Yamamoto T, Fukui G, Maeda T, Hino A, Suetomi T, Ono M, Mochozuki M, Oda T, Okuda S, Kobayashi S, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] Dantrolene Enhances Binding of Calmodulin to RyR2 in CPVT Which Mutation Located at Central Domain but Does Not Enhance That in CPVT With Mutation at CaM-like Domain. (2015)
  • Author(s): Nishimura S, Yamamoto T, Fukui G, Maeda T, Hino A, Suetomi T, Ono M, Mochozuki M, Oda T, Okuda S, Kobayashi S, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] Dantrolene Cannot Inhibit Aberrant Ca2+ Release and Arrhythmias Without Calmodulin in Pressure Overload Heart Failure. (2015)
  • Author(s): Fuykui G, Yamamoto T, Kato T, Maeda T, Nishimura S, Hino A, Suetomi T, Ono M, Mochizuki M, Oda T, Okuda, Kobayashi S, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] A Marked Increase in Myocardial Oxidative Stress Associated With Sympathetic Hyperactivity is Related to Transient Myocardial Dysfunction in Patients With Takotsubo Cardiomyopathy (2015)
  • Author(s): Nannno T, Kobayashi S, Oda S, Ishiguchi H, Myoren T, Miyazaki Y, Suetomi T, Ono M, Mochizuki M, Oda T, Okuda S, Yamada J, Okamura T, Yano M
  • Organizer: American Heart Association Scientific Meeting 2015
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] Dantrolene suppresses arrhythmogenesis by inhibition of aberrant Ca2+ release mediated by CaMKII and Ca2+ buffering in troponin T-related hypertrophic cardiomyopathy (2015)
  • Author(s): Okuda S, Fukuda M, Kato T, Nichimura S, Kobayashi S, Oda T, Yamamoto T, Yano M
  • Organizer: Japanese Society of Heart Failure
  • Place of Presentation: 大阪府大阪市 グランフロント大阪
  • Year and Date: 2015-10-22 – 2015-10-24
• [Presentation] RyR2 stabilization by inhibiting aberrant Ca2+ release mediated by CaMKII signaling and Ca2+ buffering function suppresses arrhythmogenesis in Troponin T-related familial hypertrophic cardiomyopathy (2015)
  • Author(s): Okuda S, Kato T, Fukuda M, Nichimura S, Kobayashi S, Oda T, Yamamoto T, Yano M
  • Organizer: European Society of Cardiology
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29 – 2015-09-02