Neef, Stefan and Steffens, Alexander and Pellicena, Patricia and Mustroph, Julian and Lebek, Simon and Ort, Katharina R. and Schulman, Howard and Maier, Lars S. (2018) Improvement of cardiomyocyte function by a novel pyrimidine-based CaMKII-inhibitor. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 115. pp. 73-81. ISSN 0022-2828, 1095-8584
Full text not available from this repository. (Request a copy)Abstract
Objective: Pathologically increased activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the associated Ca2+-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 CaMKII delta(C)-overexpressing mice with heart failure, AS105 effectively reduced diastolic SR Ca2+ leak by 38% to 65% as measured by Ca2+-sparks or tetracaine-sensitive shift in [Ca2+](i). Consistent with this, we found that AS105 suppressed arrhythmogenic spontaneous cardiomyocyte Ca2+-release (by 53%). Also, the ability of the SR to accumulate Ca2+ was enhanced by AS105, as indicated by improved post-rest potentiation of Ca2+-transient amplitudes and increased SR Ca2+-content in the murine cells. Accordingly, these cells had improved systolic Ca2+-transient amplitudes and contractility during basal stimulation. Importantly, CaMKII inhibition did not compromise systolic fractional Ca2+-release, diastolic SR Ca2+-reuptake via SERCA2a or Ca2+-extrusion via NCX. Conclusion: AS105 is a novel, highly potent ATP-competitive CaMKII inhibitor. In vitro, it effectively reduced SR Ca2+-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE; RETICULUM CA2+ LEAK; DILATED CARDIOMYOPATHY; CARDIAC-HYPERTROPHY; HEART-FAILURE; PHOSPHORYLATION; MODEL; MECHANISMS; EXPRESSION; ISOFORM; CaMKII; Ca2+ handling; Heart failure |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2020 07:08 |
| Last Modified: | 19 Mar 2020 07:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15103 |
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