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

Journal of Molecular and Cellular Cardiology
Stefan NeefLars S Maier

Abstract

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. 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...Continue Reading

Citations

Jul 18, 2019·Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas·C V Cruz JunhoM S Carneiro-Ramos
Nov 9, 2018·Frontiers in Physiology·Ellen R LubbersPeter J Mohler
May 29, 2018·Current Cardiology Reports·Arne A N BruyneelMark Mercola
Mar 3, 2020·Frontiers in Pharmacology·Drew NassalThomas J Hund
Aug 9, 2019·Neuron·K Ulrich Bayer, Howard Schulman
Nov 6, 2020·The Journal of Clinical Investigation·Olurotimi O MesubiMark E Anderson
Dec 15, 2019·Journal of Molecular and Cellular Cardiology·Maria J BaierAdam G Rokita
Nov 6, 2020·Evidence-based Complementary and Alternative Medicine : ECAM·Xiaomin YangYong Wang
Jan 21, 2020·Journal of Molecular and Cellular Cardiology·Michael TaklaKamalan Jeevaratnam
Feb 19, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·M TrumJ Mustroph
May 7, 2021·The Journal of General Physiology·Eef DriesCesare M Terracciano
Mar 17, 2021·The Journal of Pharmacology and Experimental Therapeutics·Yixi LiuChe-Ping Cheng
Jul 2, 2021·Oxidative Medicine and Cellular Longevity·Yun ChenWei Zhang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Atrial Filbrillation

Atrial fibrillation refers to the abnormal heart rhythm characterized by rapid and irregular beating of the atria. Here is the latest research.

Atrial Fibrillation

Atrial fibrillation is a common arrhythmia that is associated with substantial morbidity and mortality, particularly due to stroke and thromboembolism. Here is the latest research.

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.