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

Abstract

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.

• Authors: Paulina Sander, Michael Feng, Maria K Schweitzer, Fabiola Wilting, Sophie M Gutenthaler, Daniela M Arduino, Sandra Fischbach, Lisa Dreizehnter, Alessandra Moretti, Thomas Gudermann, Fabiana Perocchi, Johann Schredelseker
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 178 Issue 22 Pg. 4518-4532 (11 2021) ISSN: 1476-5381 [Electronic] England
• PMID: 34287836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Pharmaceutical Preparations
• Ryanodine Receptor Calcium Release Channel
• Ezetimibe
• Calcium
• Disulfiram

Topics

• Animals
• Arrhythmias, Cardiac (chemically induced, drug therapy, metabolism)
• Calcium (metabolism)
• Calcium Signaling
• Disulfiram (metabolism, pharmacology)
• Ezetimibe (metabolism)
• HeLa Cells
• Humans
• Mice
• Mitochondria (metabolism)
• Myocytes, Cardiac (metabolism)
• Pharmaceutical Preparations (metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Tachycardia, Ventricular (metabolism)
• Zebrafish (metabolism)