Mustroph, Julian and Wagemann, Olivia and Luecht, Charlotte M. and Trum, Maximilian and Hammer, Karin P. and Sag, Can Martin and Lebek, Simon and Tarnowski, Daniel and Reinders, Joerg and Perbellini, Filippo and Terracciano, Cesare and Schmid, Christof and Schopka, Simon and Hilker, Michael and Zausig, York and Pabel, Steffen and Sossalla, Samuel T. and Schweda, Frank and Maier, Lars S. and Wagner, Stefan (2018) Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes. ESC HEART FAILURE, 5 (4). pp. 642-648. ISSN 2055-5822,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EXCHANGER; OUTCOMES; DISEASE; TRIAL; Empagliflozin; Heart failure; CaMKII; Calcium; Ca leak |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Mar 2020 12:56 |
| Last Modified: | 05 Mar 2020 12:56 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14100 |
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