Abstract Body: Background
Doxorubicin (DOX), a commonly used anticancer agent, causes irreversible cardiac dysfunction, which remains a clinical challenge. It has been reported that DOX induces the release of Ca²⁺ through ryanodine receptor 2 (RYR2) of the sarcoplasmic reticulum (SR) and increases the Ca²⁺ level in the cytoplasm.
Objectives
we aimed to investigate whether RYR2 stabilization could suppress DOX-induced cardiomyopathy (DIC) and, if so, the optimal duration of dantrolene treatment (a pharmacological method).
Methods
We investigated the relationship between DOX cardiotoxicity and RYR2 stabilization in vivo and in vitro experiments.
Results
DOX caused calmodulin dissociation, marked Ca²⁺ leakage from RYR2, and increased oxidative stress in isolated cardiomyocytes, which were suppressed by enhancing calmodulin binding affinity of RYR2 and stabilizing its tetramer structure pharmacologically (by dantrolene) or genetically (by RYR2 V3599K mutation). In DIC model mice, cardiac function was impaired, fibrosis and TUNEL-positive cells increased, accompanied by a decrease in GRP78 and increased lipid peroxide levels, which led to endoplasmic reticulum stress and ferroptosis respectively. These cardiac dysfunctions were ameliorated by continuous dantrolene administration or RYR2 V3599K mutation. Interestingly, dantrolene was sufficiently effective for myocardial protection even when terminated 7 days after DOX administration.
Conclusions
The short-term concomitant use of dantrolene may be an innovative and clinically feasible DIC preventive strategy. Furthermore, because dantrolene is already safely used clinically as a specific drug for malignant hyperthermia, the results of this study are expected to lead to drug repositioning in the near future.