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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.*

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

Br. J. Pharmacol., DOI: 10.1111/bph.15630 (2021)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Anti-arrhythmic ; Arrhythmia ; Cpvt ; Mcu ; Micups ; Mitochondria; Calcium Uniporter; Oscillations; Fibrillation; Arrhythmias; Modulators; Kaempferol; Reticulum; Overload; Mutation; Release
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Zeitschrift British Journal of Pharmacology
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502295-001
Förderungen Bert L & N Kuggie Vallee Foundation
Initiative and Network Fund of the Helmholtz Association
Munich Center for Systems Neurology
Helmholtz-Gemeinschaft
Deutsche Forschungsgemeinschaft
DOI 10.1111/bph.15630
WOS ID WOS:000685877300001
Scopus ID 85112750108
PubMed ID 34287836
Erfassungsdatum 2021-09-13
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