Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca2+ uptake and suppress cardiac arrhythmogenesis.
Br J Pharmacol. 2021 Jul 21. doi: 10.1111/bph.15630. Epub ahead of print. PMID: 34287836.
|Authors/Editors:||Sander P, Feng M, Schweitzer MK, Wilting F, Gutenthaler SM, Arduino DM, Fischbach S, Dreizehnter L, Moretti A, Gudermann T, Perocchi F, Schredelseker J.|
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.