1. The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity.
- Author
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Lebek S, Plößl A, Baier M, Mustroph J, Tarnowski D, Lücht CM, Schopka S, Flörchinger B, Schmid C, Zausig Y, Pagratis N, Marchand B, Koltun DO, Hung WK, Ahmadyar S, Belardinelli L, Maier LS, and Wagner S
- Subjects
- Arrhythmias, Cardiac complications, Arrhythmias, Cardiac pathology, Arrhythmias, Cardiac physiopathology, Calcium metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Diastole drug effects, Heart Atria drug effects, Heart Atria physiopathology, Heart Failure complications, Heart Failure physiopathology, Humans, Myocardial Contraction drug effects, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Phosphorylation, Protein Kinase Inhibitors chemistry, Pyridines chemistry, Pyrrolidines chemistry, Sarcoplasmic Reticulum drug effects, Sarcoplasmic Reticulum metabolism, Arrhythmias, Cardiac enzymology, Calcium-Calmodulin-Dependent Protein Kinase Type 2 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology, Pyrrolidines pharmacology, Thiophenes pharmacology
- Abstract
Rationale: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential., Objective: We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680)., Methods and Results: Trabeculae were isolated from right atrial appendage biopsies of patients undergoing cardiac surgery. Premature atrial contractions (PACs) were induced by stimulation with isoproterenol (ISO, 100 nM) at increased [Ca]
o (3.5 mM). Interestingly, compared to vehicle, PACs were significantly inhibited by exposure to GS-680 (at 100 and 300 nM). GS-680 also significantly decreased early and delayed afterdepolarizations in isolated human atrial myocytes. Moreover, GS-680 (at 100 or 300 nM) significantly inhibited diastolic SR Ca leak, measured as frequency of spontaneous SR Ca release events (Ca sparks) in isolated human atrial myocytes (Fluo-4 loaded) similar to the well-established peptide CaMKII inhibitor AIP. In accordance, GS-680 significantly reduced CaMKII autophosphorylation (Western blot) but enhanced developed tension after 10 or 30 s pause of electrical stimulation (post-rest behavior). Surprisingly, we found a strong negative inotropic effect of GS-680 in atrial trabeculae at 1 Hz stimulation rate, which was not observed at 4 Hz and abolished by beta-adrenergic stimulation. In contrast, GS-680 did not impair systolic force of isolated ventricular trabeculae from explanted hearts of heart transplant recipients at 1 Hz, blunted the negative force-frequency relationship (1-3 Hz) and significantly increased the Ca transient amplitude., Conclusion: The novel ATP-competitive and selective CaMKII inhibitor GS-680 inhibits pro-arrhythmic activity in human atrium and improves contractility in failing human ventricle, which may have therapeutic implications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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