Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

Abstract

BACKGROUND Doxorubicin (Dox) is a potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. Intracellular calcium dysregulation has been reported to be involved in doxorubicin-induced cardiomyopathy (DICM). The cardioprotective role of RyR stabilizer dantrolene (Dan) on the calcium dynamics of DICM has not yet been explored. OBJECTIVE To evaluate the effects of dantrolene on intracellular calcium dysregulation and cardiac contractile function in a DICM model.METHODS Adult male C57BL/6 mice were randomized into 4 groups: (1) Control, (2) Dox Only, (3) Dan Only, and (4) Dan 1 Dox. Fractional shortening (FS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography. In addition, mice were sacrificed 2 weeks after doxorubicin injection for optical mapping of the heart in a Langendorff setup. RESULTSTreatment with Dox was associated with a reduction in both FS and LVEF at 2 weeks (P , .0001) and 4 weeks (P , .006). Dox treatment was also associated with prolongation of calcium transient durations CaTD 50 (P 5 .0005) and CaTD 80 (P , .0001) and reduction of calcium amplitude alternans ratio (P , .0001). Concomitant treatment with Dan prevented the Dox-induced decline in FS and LVEF (P , .002 at both 2 and 4 weeks). Dan also prevented Dox-induced prolongation of CaTD 50 and CaTD 80 and improved the CaT alternans ratio (P , .0001). Finally, calcium transient rise time was increased in the doxorubicin-treated group, indicating RyR2 dyssynchrony, and dantrolene prevented this prolongation (P 5 .02).CONCLUSION Dantrolene prevents cardiac contractile dysfunction following doxorubicin treatment by mitigating dysregulation of calcium dynamics.

Rhynchophylline Regulates Calcium Homeostasis by Antagonizing Ryanodine Receptor 2 Phosphorylation to Improve Diabetic Cardiomyopathy

“…Therefore, our manuscript focused on the effect of Rhy on sarcoplasmic reticulum calcium release. According to existing literature reports, DTL is a stabilizer of RyR2 that could protect cardiomyocytes by regulating intracellular calcium homeostasis ( Azam et al, 2021 ). Therefore, this chemical was chosen as a positive control drug in this study.…”

Statins Protect Against Early Stages of Doxorubicin-induced Cardiotoxicity Through the Regulation of Akt Signaling and SERCA2

“…However, given the failure of antioxidants, β-blockers and iron chelation therapies in treating DICM, a targetable mechanism underlying DICM has yet to found. Interestingly, abnormalities in the regulation of intracellular calcium (Ca 2+ ) cycling is commonly observed in the development of cardiomyopathy, in addition to exposure to doxorubicin [6][7][8][9] .…”

“…Interestingly, abnormalities in the regulation of intracellular calcium (Ca 2+ ) cycling are commonly observed in the development of cardiomyopathy, which is also often accompanied by exposure to Dox. 6 , 7 , 8 , 9 …”

Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function and prevents sudden arrhythmic death in failing hearts

“…An alternative approach would be to reduce RyR2 leak with RyR2 inhibitors, which could be a promising new therapeutic strategy against lethal arrhythmias and HF. Recent studies have shown the positive effects of the RyR2 inhibitor dantrolene on atrial fibrillation inducibility in animal models of myocardial infarction [22][23][24][25] . However, the utility of chronic inhibition of RyR2 in non-ischemic heart failure has not been studied.…”