Development of a new treatment for pulmonary hypertension by controlling calmodulin

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15686
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Yamaguchi University
• Principal Investigator: Nakamura Yoshihide 山口大学, 医学部, 助教(特命) (80933481)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 肺高血圧 / リアノジン受容体 / カルモジュリン / ダントロレン

Outline of Final Research Achievements

The aim of this study was to develop a treatment that would inhibit the progression of right ventricular hypertrophy to right heart failure even under pressure overload, thereby improving prognosis, by strengthening the binding of CaM to RyR2.
In an MCT-induced rat model, dantrolene inhibited right ventricular myocardial hypertrophy while maintaining right heart function by inhibiting the dissociation of CaM from RyR2, significantly improving prognosis.
In a pulmonary artery coarctation (PAB) rat model, administration of dantrolene inhibited right ventricular myocardial hypertrophy and maintained right heart function. However, no effect was observed in the RyR2 V3580K SD-rat that we developed, in which the affinity of CaM only for RyR2 was increased. It was thought that there was a problem with these rats themselves.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

本研究は、RyR2に対するCaMの結合親和性増強→CaM解離、Ca2+漏出抑制→右心肥大抑制→右心不全の阻止、という明確な機序に基づき、従来の肺血管抵抗でなく、右室機能保持をターゲットとした点が意義がある。PAHは今なお難病に分類され生命予後も不良な難治性疾患であり、新規治療法の開発は喫緊の課題である。この点、ダントロレンは安全性が高く、従来の血管拡張療法との併用も可能である点でも、本研究は臨床的意義がある。