Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca<sup>2+</sup> uptake and suppress cardiac arrhythmogenesis
Paulina Sander, Michael Sheng-Fu Feng, Maria K. Schweitzer, Fabiola Wilting, Sophie M. Gutenthaler, Daniela M. Arduíno, Sandra Fischbach, Lisa Dreizehnter, Alessandra Moretti, Thomas Gudermann, Fabiana Perocchi, Johann Schredelseker
Abstract
Background and Purpose Treatment of cardiac arrhythmia remains challenging due to severe side effects of common anti‐arrhythmic drugs. We previously demonstrated that mitochondrial Ca 2+ uptake in cardiomyocytes represents a promising new candidate structure for safer drug therapy. However, druggable agonists of mitochondrial Ca 2+ uptake suitable for preclinical and clinical studies are still missing. Experimental Approach Herewe screened 727 compounds with a history of use in human clinical trials in a three‐step screening approach. As a primary screening platform we used a permeabilized HeLa cell‐based mitochondrial Ca 2+ uptake assay. Hits were validated in cultured HL‐1 cardiomyocytes and finally tested for anti‐arrhythmic efficacy in three translational models: a Ca 2+ overload zebrafish model and cardiomyocytes of both a mouse model for catecholaminergic polymorphic ventricular tachycardia (CPVT) and induced pluripotent stem cell derived cardiomyocytes from a CPVT patient. Key Results We identifiedtwo candidate compounds, the clinically approved drugs ezetimibe and disulfiram, which stimulate SR‐mitochondria Ca 2+ transfer at nanomolar concentrations. This is significantly lower compared to the previously described mitochondrial Ca 2+ uptake enhancers (MiCUps) efsevin, a gating modifier of the voltage‐dependent anion channel 2, and kaempferol, an agonist of the mitochondrial Ca 2+ uniporter. Both substances restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model and significantly suppressed arrhythmogenesis in freshly isolated ventricular cardiomyocytes from a CPVT mouse model as well as induced pluripotent stem cell derived cardiomyocytes from a CPVT patient. Conclusion and Implications 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.