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J Mol Cell Cardiol. 2018 Feb;115:73-81. doi: 10.1016/j.yjmcc.2017.12.015. Epub 2017 Dec 30.

Improvement of cardiomyocyte function by a novel pyrimidine-based CaMKII-inhibitor.

Author information

1
Dept. of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.
2
Dept. of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
3
Allosteros Therapeutics, Inc., Sunnyvale, CA, USA.
4
Dept. of Thoracic, Cardiac and Vascular Surgery, University Medical Center Göttingen, Göttingen, Germany.
5
Dept. of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany. Electronic address: lars.maier@ukr.de.

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 CaMKIIδC-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 Ca2+-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.

KEYWORDS:

Ca(2+) handling; CaMKII; Heart failure

PMID:
29294328
PMCID:
PMC5820112
DOI:
10.1016/j.yjmcc.2017.12.015
[Indexed for MEDLINE]
Free PMC Article

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