Christos Tzimas1, Daniel M Johnson2, Demetrio J Santiago2, Elizabeth Vafiadaki1, Demetrios A Arvanitis1, Constantinos H Davos3, Aimilia Varela3, Nikolaos C Athanasiadis3, Constantinos Dimitriou3, Michalis Katsimpoulas3, Stephan Sonntag4, Mariya Kryzhanovska4, Doron Shmerling4, Stephan E Lehnart5, Karin R Sipido2, Evangelia G Kranias1,6, Despina Sanoudou1,7. 1. Department of Molecular Biology, Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Soranou Efessiou 4, 115 27, Athens, Greece. 2. Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium. 3. Department of Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece. 4. PolyGene AG, Rümlang, Switzerland. 5. Department of Cardiology and Pulmonology, Heart Research Center Goettingen, University Medical Center Goettingen, Goettingen, Germany. 6. Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA. 7. 4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Rimini 1, Chaidari 124 62, Greece.
Abstract
AIMS: The histidine-rich calcium-binding protein (HRC) Ser96Ala variant has previously been identified as a potential biomarker for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. Herein, the role of this variant in cardiac pathophysiology is delineated through a novel mouse model, carrying the human mutation in the homologous mouse position. METHODS AND RESULTS: The mouse HRC serine 81, homologous to human HRC serine 96, was mutated to alanine, using knock-in gene targeting. The HRC-Ser81Ala mice presented increased mortality in the absence of structural or histological abnormalities, indicating that early death may be arrhythmia-related. Indeed, under stress-but not baseline-conditions, the HRC-Ser81Ala mice developed ventricular arrhythmias, whilst at the cardiomyocyte level they exhibited increased occurrence of triggered activity. Cardiac contraction was decreased in vivo, ex vivo, and in vitro. Additionally, Ca2+ transients and SR Ca2+ load were both reduced suggesting that cytosolic Ca2+ overload is not the underlying proarrhythmic mechanism. Interestingly, total SR Ca2+ leak was increased in HRC-Ser81Ala cardiomyocytes, without an increase in Ca2+ spark and wave frequency. However, Ca2+ wave propagation was significantly slower and the duration of the associated Na/Ca exchange current was increased. Moreover, action potential duration was also increased. Notably, Ca2+/Calmodulin kinase II (CaMKII) phosphorylation of the ryanodine receptor was increased, whilst KN-93, an inhibitor of CaMKII, reduced the occurrence of arrhythmias. CONCLUSIONS: The homologous mutation Ser81Ala in HRC in mice, corresponding to Ser96Ala in humans, is associated with sudden death and depressed cardiac function. Ventricular arrhythmias are related to abnormal Ca2+ cycling across the SR. The data further support a role for CaMKII with the perspective to treat arrhythmias through CaMKII inhibition. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The histidine-rich calcium-binding protein (HRC) Ser96Ala variant has previously been identified as a potential biomarker for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. Herein, the role of this variant in cardiac pathophysiology is delineated through a novel mouse model, carrying the human mutation in the homologous mouse position. METHODS AND RESULTS: The mouse HRC serine 81, homologous to human HRC serine 96, was mutated to alanine, using knock-in gene targeting. The HRC-Ser81Ala mice presented increased mortality in the absence of structural or histological abnormalities, indicating that early death may be arrhythmia-related. Indeed, under stress-but not baseline-conditions, the HRC-Ser81Ala mice developed ventricular arrhythmias, whilst at the cardiomyocyte level they exhibited increased occurrence of triggered activity. Cardiac contraction was decreased in vivo, ex vivo, and in vitro. Additionally, Ca2+ transients and SR Ca2+ load were both reduced suggesting that cytosolic Ca2+ overload is not the underlying proarrhythmic mechanism. Interestingly, total SR Ca2+ leak was increased in HRC-Ser81Ala cardiomyocytes, without an increase in Ca2+ spark and wave frequency. However, Ca2+ wave propagation was significantly slower and the duration of the associated Na/Ca exchange current was increased. Moreover, action potential duration was also increased. Notably, Ca2+/Calmodulin kinase II (CaMKII) phosphorylation of the ryanodine receptor was increased, whilst KN-93, an inhibitor of CaMKII, reduced the occurrence of arrhythmias. CONCLUSIONS: The homologous mutation Ser81Ala in HRC in mice, corresponding to Ser96Ala in humans, is associated with sudden death and depressed cardiac function. Ventricular arrhythmias are related to abnormal Ca2+ cycling across the SR. The data further support a role for CaMKII with the perspective to treat arrhythmias through CaMKII inhibition. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Joachim A Behar; Aviv A Rosenberg; Ori Shemla; Kevin R Murphy; Gideon Koren; George E Billman; Yael Yaniv Journal: Front Physiol Date: 2018-08-02 Impact factor: 4.566
Authors: Adam J Pollak; Canzhao Liu; Aparna Gudlur; Joshua E Mayfield; Nancy D Dalton; Yusu Gu; Ju Chen; Joan Heller Brown; Patrick G Hogan; Sandra E Wiley; Kirk L Peterson; Jack E Dixon Journal: Elife Date: 2018-12-06 Impact factor: 8.140
Authors: Demetrios A Arvanitis; Elizabeth Vafiadaki; Daniel M Johnson; Evangelia G Kranias; Despina Sanoudou Journal: Front Physiol Date: 2018-09-27 Impact factor: 4.566
Authors: Eric L Bogenschutz; Zac D Fox; Andrew Farrell; Julia Wynn; Barry Moore; Lan Yu; Gudrun Aspelund; Gabor Marth; Mark Yandell; Yufeng Shen; Wendy K Chung; Gabrielle Kardon Journal: HGG Adv Date: 2020-08-25