PuSH - Publikationsserver des Helmholtz Zentrums München

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 Gold (Paid Option)
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.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Anti-arrhythmic ; Arrhythmia ; Cpvt ; Mcu ; Micups ; Mitochondria; Calcium Uniporter; Oscillations; Fibrillation; Arrhythmias; Modulators; Kaempferol; Reticulum; Overload; Mutation; Release
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
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Förderungen Bert L & N Kuggie Vallee Foundation
Initiative and Network Fund of the Helmholtz Association
Munich Center for Systems Neurology
Helmholtz-Gemeinschaft
Deutsche Forschungsgemeinschaft