Development of novel molecular targeted therapy by stabilizing cardiac ryanodine receptors in hypertrophic cardiomyopathy

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08076
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamaguchi University
• Principal Investigator: OKUDA Shinichi 山口大学, 医学部附属病院, 助教 (90530212)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 肥大型心筋症 / リアノジン受容体 / カルシウム依存性カルモジュリンキナーゼ / カルモジュリン

Outline of Final Research Achievements

In hypertrophic cardiomyopathy (HCM), there is a high-risk group that causes sudden death due to lethal arrhythmia along with cardiac hypertrophy; however, no disease-specific drug therapy was currently presented. This study focused on the increase in intramyocardial Ca2+ concentration during diastole, which is closely related to lethal arrhythmias in HCM. The results showed that Ca2+ concentration increases during diastole due to abnormal Ca2+ leakage via Ca2+/calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor (RyR2) and subsequent dissociation of calmodulin from RyR2 and that RyR2 stabilization suppresses Ca2+ leakage. These results suggest that RyR2 stabilization may prevent the increase in diastolic Ca2+ concentration by improving myocardial sarcoplasmic reticulum function, thereby preventing the induction of lethal arrhythmias.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

肥大型心筋症(HCM)では著明な心肥大とともに致死性不整脈による突然死を来すハイリスク群が存在する。現在、不整脈発生時には植え込み型除細動器による電気的除細動や一般的な心室性不整脈に対する薬物療法が行われるが、疾患特異的な薬物療法は存在しない。本研究では、HCMでの致死性不整脈に深く関わる心筋細胞内カルシウム動態異常に着目した。その結果、カルシウム/カルモジュリン依存性プロテインキナーゼII活性化を介したリアノジン受容体(RyR2)からの異常なカルシウム放出が病態の一因で、RyR2安定化により病態を改善し得る可能性がある事が判明した。この知見は、将来の治療法につながりうる重要な成果である。