Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts

Xiaowei Zhong; Bo Sun; Alexander Vallmitjana; Tao Mi; Wenting Guo; Mingke Ni; Ruiwu Wang; Ang Guo; Henry J Duff; Anne M Gillis; Long-Sheng Song; Leif Hove-Madsen; Raul Benitez; S R Wayne Chen

doi:10.1042/BCJ20160606

$Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts$

Journal article

Open access

Peer reviewed

Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts

Xiaowei Zhong, Bo Sun, Alexander Vallmitjana, Tao Mi, Wenting Guo, Mingke Ni, Ruiwu Wang, Ang Guo, Henry J Duff, Anne M Gillis, …

The Biochemical journal, Vol.473(21), pp.3951-3964

11/01/2016

DOI: 10.1042/BCJ20160606

PMCID: PMC5522810

PMID: 27582498

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Abstract

Beat-to-beat alternations in the amplitude of the cytosolic Ca transient (Ca alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca release channel responsible for cytosolic Ca transients, in cardiac alternans. Using a unique mouse model harboring a suppression-of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca release refractoriness and enhanced propensity for Ca alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca alternans in RyR2-SOF hearts, whereas carvedilol, a β-blocker that suppresses RyR2 activity and CPVT, promoted Ca alternans in these hearts. Thus, RyR2 function is an important determinant of Ca , APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.

Animals

Disease Models, Animal

Electrocardiography

Heart - drug effects

Heart - physiopathology

Isoproterenol - pharmacology

Mice

Mutation - genetics

Myocardium - metabolism

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - metabolism

Ryanodine Receptor Calcium Release Channel - genetics

Ryanodine Receptor Calcium Release Channel - metabolism

Sarcoplasmic Reticulum - drug effects

Sarcoplasmic Reticulum - metabolism

Tachycardia - genetics

Tachycardia - metabolism

Tachycardia, Ventricular - genetics

Tachycardia, Ventricular - metabolism

Details

Title: Subtitle: Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts
Creators: Xiaowei Zhong - Libin Cardiovascular Institute of Alberta
Bo Sun - Libin Cardiovascular Institute of Alberta
Alexander Vallmitjana - Universitat Politècnica de Catalunya
Tao Mi - Libin Cardiovascular Institute of Alberta
Wenting Guo - Libin Cardiovascular Institute of Alberta
Mingke Ni - Libin Cardiovascular Institute of Alberta
Ruiwu Wang - Libin Cardiovascular Institute of Alberta
Ang Guo - University of Iowa
Henry J Duff - Libin Cardiovascular Institute of Alberta
Anne M Gillis - Libin Cardiovascular Institute of Alberta
Long-Sheng Song - University of Iowa
Leif Hove-Madsen - Hospital de Sant Pau
Raul Benitez - Universitat Politècnica de Catalunya
S R Wayne Chen - Libin Cardiovascular Institute of Alberta
Resource Type: Journal article
Publication Details: The Biochemical journal, Vol.473(21), pp.3951-3964
DOI: 10.1042/BCJ20160606
PMID: 27582498
PMCID: PMC5522810
ISSN: 0264-6021
eISSN: 1470-8728
Grant note: R01 HL130346 / NHLBI NIH HHS I01 BX002334 / BLRD VA R01 HL090905 / NHLBI NIH HHS
Language: English
Date published: 11/01/2016
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984288731702771

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