The HRC-Ser81Ala mutation in mice, corresponding to the human Ser96Ala variant, was associated with increased mortality, depressed cardiac function, and stress-induced ventricular arrhythmias.
The homologous mutation Ser81Ala in HRC in mice is associated with sudden death, depressed cardiac function, and ventricular arrhythmias related to abnormal Ca2+ cycling, supporting a potential therapeutic role for CaMKII inhibition.
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.
Tzimas et al. (Tue,) conducted a other in Ventricular arrhythmias and sudden cardiac death. HRC-Ser81Ala mutation vs. Wild-type mice was evaluated on Mortality and ventricular arrhythmias. The HRC-Ser81Ala mutation in mice, corresponding to the human Ser96Ala variant, was associated with increased mortality, depressed cardiac function, and stress-induced ventricular arrhythmias.