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Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca 2+ uptake and suppress cardiac arrhythmogenesis
Author(s) -
Sander Paulina,
Feng Michael,
Schweitzer Maria K.,
Wilting Fabiola,
Gutenthaler Sophie M.,
Arduino Daniela M.,
Fischbach Sandra,
Dreizehnter Lisa,
Moretti Alessandra,
Gudermann Thomas,
Perocchi Fabiana,
Schredelseker Johann
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15630
Subject(s) - catecholaminergic polymorphic ventricular tachycardia , pharmacology , induced pluripotent stem cell , vdac1 , medicine , mitochondrion , chemistry , biology , ryanodine receptor , microbiology and biotechnology , biochemistry , calcium , ryanodine receptor 2 , escherichia coli , bacterial outer membrane , gene , embryonic stem cell
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.