Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes

URN to cite this document:: urn:nbn:de:bvb:355-epub-377616
DOI to cite this document:: 10.5283/epub.37761

Mustroph, Julian ; Wagemann, Olivia ; Lücht, Charlotte M. ; Trum, Maximilian ; Hammer, Karin P. ; Sag, Can Martin ; Lebek, Simon ; Tarnowski, Daniel ; Reinders, Jörg ; Perbellini, Filippo ; Terracciano, Cesare ; Schmid, Christof ; Schopka, Simon ; Hilker, Michael ; Zausig, York ; Pabel, Steffen ; Sossalla, Samuel T. ; Schweda, Frank ; Maier, Lars S. ; Wagner, Stefan

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Date of publication of this fulltext: 24 Sep 2018 15:02

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AimsThe EMPA-REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca2+-dependent activation of Ca2+/calmodulin-dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin reduces CaMKII- activity and improves Ca2+-handling in human and murine ventricular myocytes. Methods and resultsMyocytes from wild-type mice, mice with transverse aortic constriction (TAC) as a model of HF, and human failing ventricular myocytes were exposed to empagliflozin (1mol/L) or vehicle. CaMKII activity was assessed by CaMKII-histone deacetylase pulldown assay. Ca2+ spark frequency (CaSpF) as a measure of sarcoplasmic reticulum (SR) Ca2+ leak was investigated by confocal microscopy. [Na+](i) was measured using Na+/Ca2+-exchanger (NCX) currents (whole-cell patch clamp). Compared with vehicle, 24h empagliflozin exposure of murine myocytes reduced CaMKII activity (1.60.7 vs. 4.2 +/- 0.9, P<0.05, n=10 mice), and also CaMKII-dependent ryanodine receptor phosphorylation (0.8 +/- 0.1 vs. 1.0 +/- 0.1, P<0.05, n=11 mice), with similar results upon TAC. In murine myocytes, empagliflozin reduced CaSpF (TAC: 1.7 +/- 0.3 vs. 2.5 +/- 0.4 1/100m(-1)s(-1), P<0.05, n=4 mice) but increased SR Ca2+ load and Ca2+ transient amplitude. Importantly, empagliflozin also significantly reduced CaSpF in human failing ventricular myocytes (1 +/- 0.2 vs. 3.3 +/- 0.9, P<0.05, n=4 patients), while Ca2+ transient amplitude was increased (F/F-0: 0.53 +/- 0.05 vs. 0.36 +/- 0.02, P<0.05, n=3 patients). In contrast, 30min exposure with empagliflozin did not affect CaMKII activity nor Ca2+-handling but significantly reduced [Na+](i). ConclusionsWe show for the first time that empagliflozin reduces CaMKII activity and CaMKII-dependent SR Ca2+ leak. Reduced Ca2+ leak and improved Ca2+ transients may contribute to the beneficial effects of empagliflozin in HF.

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