Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca2+ uptake and suppress cardiac arrhythmogenesis
Autor: | Thomas Gudermann, Johann Schredelseker, Alessandra Moretti, Fabiola Wilting, Sophie M. Gutenthaler, Michael Feng, Fabiana Perocchi, Maria K. Schweitzer, Lisa Dreizehnter, Paulina Sander, Sandra Fischbach, Daniela M. Arduino |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Pharmacology
Agonist medicine.drug_class business.industry Cardiac arrhythmia Mitochondrion Catecholaminergic polymorphic ventricular tachycardia medicine.disease Ezetimibe Disulfiram medicine Uniporter Induced pluripotent stem cell business Anti-arrhythmic Arrhythmia Cpvt Mcu Micups Mitochondria medicine.drug |
Zdroj: | Br. J. Pharmacol., DOI: 10.1111/bph.15630 (2021) |
Popis: | BACKGROUND AND PURPOSE 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. 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 Ca2+ uptake assay. Hits were validated in cultured HL-1 cardiomyocytes and finally tested for anti-arrhythmic efficacy in three translational models: a Ca2+ 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 Ca2+ transfer at nanomolar concentrations. This 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. 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. |
Databáze: | OpenAIRE |
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