Empagliflozin reduces Ca/calmodulin‐dependent kinase II activity in isolated ventricular cardiomyocytes. (3rd August 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: ESC heart failure. Volume 5:Number 4(2018)
• Page Start: 642
• Page End: 648
• Publication Date: 2018-08-03
• Subjects: Empagliflozin -- Heart failure -- CaMKII -- Calcium -- Ca leak; Heart failure -- Periodicals; 616.129005
• DOI: 10.1002/ehf2.12336
• Languages: English
• ISSNs: 2055-5822

Abstract

Abstract: Aims: The EMPA‐REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca 2+ ‐dependent activation of Ca 2+ /calmodulin‐dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin reduces CaMKII‐ activity and improves Ca 2+ ‐handling in human and murine ventricular myocytes. Methods and results: Myocytes from wild‐type mice, mice with transverse aortic constriction (TAC) as a model of HF, and human failing ventricular myocytes were exposed to empagliflozin (1 μmol/L) or vehicle. CaMKII activity was assessed by CaMKII–histone deacetylase pulldown assay. Ca 2+ spark frequency (CaSpF) as a measure of sarcoplasmic reticulum (SR) Ca 2+ leak was investigated by confocal microscopy. [Na + ]i was measured using Na + /Ca 2+ ‐exchanger (NCX) currents (whole‐cell patch clamp). Compared with vehicle, 24 h empagliflozin exposure of murine myocytes reduced CaMKII activity (1.6 ± 0.7 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 1/100 μm −1 s −1, P < 0.05, n = 4 mice) but increased SR Ca 2+ load and Ca 2+ 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 Ca 2+ transient amplitude was increased (F/F0 : 0.53 ± 0.05 vs. 0.36 ± 0.02, P < 0.05, n = 3 patients). In contrast, 30 min exposure with empagliflozin did not affect CaMKII activity nor Ca 2+ ‐handling but significantly reduced [Na + ]i . Conclusions: We show for the first time that empagliflozin reduces CaMKII activity and CaMKII‐dependent SR Ca 2+ leak. Reduced Ca 2+ leak and improved Ca 2+ transients may contribute to the beneficial effects of empagliflozin in HF.