Exploration of treatments common to heart failure and atherosclerosis focusing on ryanodine receptor bound calmodulin

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08540
• 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: Oda Tetsuro 山口大学, 医学部附属病院, 助教 (40569290)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 小胞体ストレス / カルモジュリン / リアノジン受容体 / 形質転換 / カルシウムハンドリング

Outline of Final Research Achievements

Here, we used mouse VSMC line to assess whether CaM-RyR play a pivotal role in VSMCs phenotypic switching, which caused by ER stress and whether dantrolene (DAN), which enhances the binding affinity of CaM to RyR, affects VSMCs phenotypic switching. Tunicamycin (TM) was used to mimic ER stress. TM-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulates phenotypic switching through activation of MEF2 and KLF5. DAN suppressed TM-induced apoptosis, ER stress (restoring ER Ca2+ content), and phenotypic switching of VSMCs. Suramin, which directly delete CaM from RyR2, promoted nuclear CaM accumulation with parallel VSMCs phenotypic switching and DAN prevented these.
ER stress causes CaM translocation to the nucleus and driving VSMCs phenotypic switching. Thus, restoring CaM-RyR binding affinity may be a therapeutic target for atherosclerosis.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

リアノジン受容体(RyR)に結合しているカルモジュリン(CaM)の結合親和性を高めることは、血管平滑筋細胞の小胞体ストレスを軽減させ、小胞体ストレス増加時にみられる動脈硬化促進の一端を担っている血管平滑筋細胞の形質転換を抑制することで、動脈硬化症の進展を抑制している可能性が示唆された。筆者らはRyR結合CaMの結合親和性を高めるダントロレンが心不全発症・進展を抑制することをすでに報告しており、RyR結合CaMに注目することで、心不全と動脈硬化症とを同時に治療できる新しい治療法の開発が期待される。