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Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation
- Source :
- Cardiovascular Research. 87:50-59
- Publication Year :
- 2010
- Publisher :
- Oxford University Press (OUP), 2010.
-
Abstract
- Mutations in the cardiac ryanodine receptor Ca(2+) release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) release in response to SR Ca(2+) overload during beta-adrenergic stimulation. However, whether elevated SR Ca(2+) content--in the absence of protein kinase A activation--affects RyR2 function and arrhythmogenesis in CPVT remains elusive.Isolated murine ventricular myocytes harbouring a human RyR2 mutation (RyR2(R4496C+/-)) associated with CPVT were investigated in the absence and presence of 1 micromol/L JTV-519 (RyR2 stabilizer) followed by 100 micromol/L ouabain intervention to increase cytosolic [Na(+)] and SR Ca(2+) load. Changes in membrane potential and intracellular [Ca(2+)] were monitored with whole-cell patch-clamping and confocal Ca(2+) imaging, respectively. At baseline, action potentials (APs), Ca(2+) transients, fractional SR Ca(2+) release, and SR Ca(2+) load were comparable in wild-type (WT) and RyR2(R4496C+/-) myocytes. Ouabain evoked significant increases in diastolic [Ca(2+)], peak systolic [Ca(2+)], fractional SR Ca(2+) release, and SR Ca(2+) content that were quantitatively similar in WT and RyR2(R4496C+/-) myocytes. Ouabain also induced arrhythmogenic events, i.e. spontaneous Ca(2+) waves, delayed afterdepolarizations and spontaneous APs, in both groups. However, the ouabain-induced increase in the frequency of arrhythmogenic events was dramatically larger in RyR2(R4496C+/-) when compared with WT myocytes. JTV-519 greatly reduced the frequency of ouabain-induced arrhythmogenic events.The elevation of SR Ca(2+) load--in the absence of beta-adrenergic stimulation--is sufficient to increase the propensity for triggered arrhythmias in RyR2(R4496C+/-) cardiomyocytes. Stabilization of RyR2 by JTV-519 effectively reduces these triggered arrhythmias.
- Subjects :
- Male
medicine.medical_specialty
Patch-Clamp Techniques
Time Factors
Thiazepines
Physiology
Action Potentials
Mice, Transgenic
Biology
Catecholaminergic polymorphic ventricular tachycardia
Ryanodine receptor 2
Ouabain
Mice
chemistry.chemical_compound
Catecholamines
Physiology (medical)
Internal medicine
medicine
Animals
Humans
Myocyte
Myocytes, Cardiac
Calcium Signaling
Gene Knock-In Techniques
Patch clamp
Enzyme Inhibitors
Phosphorylation
Membrane potential
Microscopy, Confocal
Ryanodine receptor
Sodium
Editorials
Ryanodine Receptor Calcium Release Channel
JTV-519
medicine.disease
Sarcoplasmic Reticulum
Endocrinology
chemistry
Mutation
Tachycardia, Ventricular
cardiovascular system
Calcium
Female
Sodium-Potassium-Exchanging ATPase
Cardiology and Cardiovascular Medicine
medicine.drug
Subjects
Details
- ISSN :
- 17553245 and 00086363
- Volume :
- 87
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Research
- Accession number :
- edsair.doi.dedup.....e7f299a96fac8d6c6da2bc926b4cdc57