PUBLICATION

Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca2+ uptake and suppress cardiac arrhythmogenesis

Authors
Sander, P., Feng, M., Schweitzer, M.K., Wilting, F., Gutenthaler, S.M., Arduino, D.M., Fischbach, S., Dreizehnter, L., Moretti, A., Gudermann, T., Perocchi, F., Schredelseker, J.
ID
ZDB-PUB-210722-3
Date
2021
Source
British journal of pharmacology   178(22): 4518-4532 (Journal)
Registered Authors
Schredelseker, Johann
Keywords
Anti-arrhythmic, Arrhythmia, CPVT, MCU, MiCUps, Mitochondria
MeSH Terms
  • Ezetimibe/metabolism
  • Calcium/metabolism
  • Ryanodine Receptor Calcium Release Channel/metabolism
  • Calcium Signaling
  • Pharmaceutical Preparations*/metabolism
  • Animals
  • Mice
  • HeLa Cells
  • Mitochondria/metabolism
  • Tachycardia, Ventricular*/metabolism
  • Humans
  • Disulfiram/metabolism
  • Disulfiram/pharmacology
  • Myocytes, Cardiac/metabolism
  • Arrhythmias, Cardiac/chemically induced
  • Arrhythmias, Cardiac/drug therapy
  • Arrhythmias, Cardiac/metabolism
  • Zebrafish/metabolism
(all 18)
PubMed
34287836 Full text @ Br. J. Pharmacol.
Abstract
Treatment of cardiac arrhythmia remains challenging due to severe side effects of common anti-arrhythmic drugs. We previously demonstrated that mitochondrial Ca2+ uptake in cardiomyocytes represents a promising new candidate structure for safer drug therapy. However, druggable agonists of mitochondrial Ca2+ uptake suitable for preclinical and clinical studies are still missing. Here, we screened 727 compounds with a history of use in human clinical trials for their potential to enhance mitochondrial Ca2+ uptake. As a primary screening platform we used a previously validated permeabilized HeLa cell-based assay and identified three candidates. To reassess these hits in a cardiac system we tested them in cultured cardiomyocytes and found that two compounds, the FDA and EMA approved drugs ezetimibe and disulfiram, were effective in stimulating SR-mitochondria Ca2+ transfer at nanomolar concentrations, which is significantly lower compared to the previously described mitochondrial Ca2+ uptake enhancers (MiCUps) efsevin, a gating modifier of the voltage-dependent anion channel 2, and kaempferol, an agonist of the mitochondrial Ca2+ uniporter. Evaluation of their efficacy in translational models revealed that both substances significantly suppressed arrhythmogenesis in an in vivo zebrafish Ca2+ overload model and suppressed arrhythmogenic signals in both, freshly isolated ventricular cardiomyocytes of a mouse model for catecholaminergic polymorphic ventricular tachycardia (CPVT) and induced pluripotent stem cell derived cardiomyocytes from a CPVT patient. Taken together we identified ezetimibe and disulfiram as novel MiCUPs and efficient suppressors of arrhythmogenesis and as such as promising candidates for future preclinical and clinical studies.
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Citation
Sander, P., Feng, M., Schweitzer, M.K., Wilting, F., Gutenthaler, S.M., Arduino, D.M., Fischbach, S., Dreizehnter, L., Moretti, A., Gudermann, T., Perocchi, F., Schredelseker, J. (2021) Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca2+ uptake and suppress cardiac arrhythmogenesis. British journal of pharmacology. 178(22):4518-4532.