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The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity

Sudden unexpected cardiac death (SCD) accounts for up to half of all-cause mortality of heart failure patients. Standardized cardiology tools such as electrocardiography, cardiac imaging, electrophysiological and serum biomarkers cannot accurately predict which patients are at risk of life-threateni...

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Autores principales: Arvanitis, Demetrios A., Vafiadaki, Elizabeth, Johnson, Daniel M., Kranias, Evangelia G., Sanoudou, Despina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171002/
https://www.ncbi.nlm.nih.gov/pubmed/30319456
http://dx.doi.org/10.3389/fphys.2018.01379
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author Arvanitis, Demetrios A.
Vafiadaki, Elizabeth
Johnson, Daniel M.
Kranias, Evangelia G.
Sanoudou, Despina
author_facet Arvanitis, Demetrios A.
Vafiadaki, Elizabeth
Johnson, Daniel M.
Kranias, Evangelia G.
Sanoudou, Despina
author_sort Arvanitis, Demetrios A.
collection PubMed
description Sudden unexpected cardiac death (SCD) accounts for up to half of all-cause mortality of heart failure patients. Standardized cardiology tools such as electrocardiography, cardiac imaging, electrophysiological and serum biomarkers cannot accurately predict which patients are at risk of life-threatening arrhythmic episodes. Recently, a common variant of the histidine-rich calcium binding protein (HRC), the Ser96Ala, was identified as a potent biomarker of malignant arrhythmia triggering in these patients. HRC has been shown to be involved in the regulation of cardiac sarcoplasmic reticulum (SR) Ca(2+) cycling, by binding and storing Ca(2+) in the SR, as well as interacting with the SR Ca(2+) uptake and release complexes. The underlying mechanisms, elucidated by studies at the molecular, biochemical, cellular and intact animal levels, indicate that transversion of Ser96 to Ala results in abolishment of an HRC phosphorylation site by Fam20C kinase and dysregulation of SR Ca(2+) cycling. This is mediated through aberrant SR Ca(2+) release by the ryanodine receptor (RyR2) quaternary complex, due to the impaired HRC/triadin interaction, and depressed SR Ca(2+) uptake by the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA2) pump, due to the impaired HRC/SERCA2 interaction. Pharmacological intervention with KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), in the HRC Ser96Ala mouse model, reduced the occurrence of malignant cardiac arrhythmias. Herein, we summarize the current evidence on the pivotal role of HRC in the regulation of cardiac rhythmicity and the importance of HRC Ser96Ala as a genetic modifier for arrhythmias in the setting of heart failure.
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spelling pubmed-61710022018-10-12 The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity Arvanitis, Demetrios A. Vafiadaki, Elizabeth Johnson, Daniel M. Kranias, Evangelia G. Sanoudou, Despina Front Physiol Physiology Sudden unexpected cardiac death (SCD) accounts for up to half of all-cause mortality of heart failure patients. Standardized cardiology tools such as electrocardiography, cardiac imaging, electrophysiological and serum biomarkers cannot accurately predict which patients are at risk of life-threatening arrhythmic episodes. Recently, a common variant of the histidine-rich calcium binding protein (HRC), the Ser96Ala, was identified as a potent biomarker of malignant arrhythmia triggering in these patients. HRC has been shown to be involved in the regulation of cardiac sarcoplasmic reticulum (SR) Ca(2+) cycling, by binding and storing Ca(2+) in the SR, as well as interacting with the SR Ca(2+) uptake and release complexes. The underlying mechanisms, elucidated by studies at the molecular, biochemical, cellular and intact animal levels, indicate that transversion of Ser96 to Ala results in abolishment of an HRC phosphorylation site by Fam20C kinase and dysregulation of SR Ca(2+) cycling. This is mediated through aberrant SR Ca(2+) release by the ryanodine receptor (RyR2) quaternary complex, due to the impaired HRC/triadin interaction, and depressed SR Ca(2+) uptake by the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA2) pump, due to the impaired HRC/SERCA2 interaction. Pharmacological intervention with KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), in the HRC Ser96Ala mouse model, reduced the occurrence of malignant cardiac arrhythmias. Herein, we summarize the current evidence on the pivotal role of HRC in the regulation of cardiac rhythmicity and the importance of HRC Ser96Ala as a genetic modifier for arrhythmias in the setting of heart failure. Frontiers Media S.A. 2018-09-27 /pmc/articles/PMC6171002/ /pubmed/30319456 http://dx.doi.org/10.3389/fphys.2018.01379 Text en Copyright © 2018 Arvanitis, Vafiadaki, Johnson, Kranias and Sanoudou. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Arvanitis, Demetrios A.
Vafiadaki, Elizabeth
Johnson, Daniel M.
Kranias, Evangelia G.
Sanoudou, Despina
The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity
title The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity
title_full The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity
title_fullStr The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity
title_full_unstemmed The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity
title_short The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity
title_sort histidine-rich calcium binding protein in regulation of cardiac rhythmicity
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171002/
https://www.ncbi.nlm.nih.gov/pubmed/30319456
http://dx.doi.org/10.3389/fphys.2018.01379
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