| First Author | Neef S | Year | 2018 |
| Journal | J Mol Cell Cardiol | Volume | 115 |
| Pages | 73-81 | PubMed ID | 29294328 |
| Mgi Jnum | J:259432 | Mgi Id | MGI:6117658 |
| Doi | 10.1016/j.yjmcc.2017.12.015 | Citation | Neef S, et al. (2018) Improvement of cardiomyocyte function by a novel pyrimidine-based CaMKII-inhibitor. J Mol Cell Cardiol 115:73-81 |
| abstractText | OBJECTIVE: Pathologically increased activity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and the associated Ca(2+)-leak from the sarcoplasmic reticulum are recognized to be important novel pharmacotherapeutic targets in heart failure and cardiac arrhythmias. However, CaMKII-inhibitory compounds for therapeutic use are still lacking. We now report on the cellular and molecular effects of a novel pyrimidine-based CaMKII inhibitor developed towards clinical use. METHODS AND RESULTS: Our findings demonstrate that AS105 is a high-affinity ATP-competitive CaMKII-inhibitor that by its mode of action is also effective against autophosphorylated CaMKII (in contrast to the commonly used allosteric CaMKII-inhibitor KN-93). In isolated atrial cardiomyocytes from human donors and ventricular myocytes from CaMKIIdeltaC-overexpressing mice with heart failure, AS105 effectively reduced diastolic SR Ca(2+) leak by 38% to 65% as measured by Ca(2+)-sparks or tetracaine-sensitive shift in [Ca(2+)]i. Consistent with this, we found that AS105 suppressed arrhythmogenic spontaneous cardiomyocyte Ca(2+)-release (by 53%). Also, the ability of the SR to accumulate Ca(2+) was enhanced by AS105, as indicated by improved post-rest potentiation of Ca(2+)-transient amplitudes and increased SR Ca(2+)-content in the murine cells. Accordingly, these cells had improved systolic Ca(2+)-transient amplitudes and contractility during basal stimulation. Importantly, CaMKII inhibition did not compromise systolic fractional Ca(2+)-release, diastolic SR Ca(2+)-reuptake via SERCA2a or Ca(2+)-extrusion via NCX. CONCLUSION: AS105 is a novel, highly potent ATP-competitive CaMKII inhibitor. In vitro, it effectively reduced SR Ca(2+)-leak, thus improving SR Ca(2+)-accumulation and reducing cellular arrhythmogenic correlates, without negatively influencing excitation-contraction coupling. These findings further validate CaMKII as a key target in cardiovascular disease, implicated by genetic, allosteric inhibitors, and pseudo-substrate inhibitors. |
