RGD Reference Report - Arrhythmogenic adverse effects of cardiac glycosides are mediated by redox modification of ryanodine receptors. - Rat Genome Database

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Arrhythmogenic adverse effects of cardiac glycosides are mediated by redox modification of ryanodine receptors.

Authors: Ho, HT  Stevens, SC  Terentyeva, R  Carnes, CA  Terentyev, D  Gyorke, S 
Citation: Ho HT, etal., J Physiol. 2011 Oct 1;589(Pt 19):4697-708. Epub 2011 Aug 1.
RGD ID: 7175254
Pubmed: PMID:21807619   (View Abstract at PubMed)
PMCID: PMC3213417   (View Article at PubMed Central)
DOI: DOI:10.1113/jphysiol.2011.210005   (Journal Full-text)

The therapeutic use of cardiac glycosides (CGs), agents commonly used in treating heart failure (HF), is limited by arrhythmic toxicity. The adverse effects of CGs have been attributed to excessive accumulation of intracellular Ca(2+) resulting from inhibition of Na(+)/K(+)-ATPase ion transport activity. However, CGs are also known to increase intracellular reactive oxygen species (ROS), which could contribute to arrhythmogenesis through redox modification of cardiac ryanodine receptors (RyR2s). Here we sought to determine whether modification of RyR2s by ROS contributes to CG-dependent arrhythmogenesis and examine the relevant sources of ROS. In isolated rat ventricular myocytes, the CG digitoxin (DGT) increased the incidence of arrhythmogenic spontaneous Ca(2+) waves, decreased the sarcoplasmic reticulum (SR) Ca(2+) load, and increased both ROS and RyR2 thiol oxidation. Additionally, pretreatment with DGT increased spark frequency in permeabilized myocytes. These effects on Ca(2+) waves and sparks were prevented by the antioxidant N-(2-mercaptopropionyl) glycine (MPG). The CG-dependent increases in ROS, RyR2 oxidation and arrhythmogenic propensity were reversed by inhibitors of NADPH oxidase, mitochondrial ATP-dependent K(+) channels (mito-K(ATP)) or permeability transition pore (PTP), but not by inhibition of xanthine oxidase. These results suggest that the arrhythmogenic adverse effects of CGs involve alterations in RyR2 function caused by oxidative changes in the channel structure by ROS. These CG-dependent effects probably involve release of ROS from mitochondria possibly mediated by NADPH oxidase.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
sarcoplasmic reticulum calcium ion transport  IMP 7175254 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
sarcoplasmic reticulum  IDA 7175254 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ryanodine-sensitive calcium-release channel activity  IMP 7175254 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ryr2  (ryanodine receptor 2)


Additional Information