Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Sedej, S; Heinzel, FR; Walther, S; Dybkova, N; Wakula, P; Groborz, J; Gronau, P; Maier, LS; Vos, MA; Lai, FA; Napolitano, C; Priori, SG; Kockskämper, J; Pieske, B.
Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation.
Cardiovasc Res. 2010; 87(1):50-59
Doi: 10.1093/cvr/cvq007
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- Führende Autor*innen der Med Uni Graz
- Pieske Burkert Mathias
- Sedej Simon
- Co-Autor*innen der Med Uni Graz
- Heinzel Frank
- Kockskämper Jens
- Wakula-Heinzel Paulina
- Walther Stefanie
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- Abstract:
- Mutations in the cardiac ryanodine receptor Ca2+ release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2-mediated sarcoplasmic reticulum (SR) Ca2+ release in response to SR Ca2+ overload during beta-adrenergic stimulation. However, whether elevated SR Ca2+ 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 mu mol/L JTV-519 (RyR2 stabilizer) followed by 100 mu mol/L ouabain intervention to increase cytosolic [Na+] and SR Ca2+ load. Changes in membrane potential and intracellular [Ca2+] were monitored with whole-cell patch-clamping and confocal Ca2+ imaging, respectively. At baseline, action potentials (APs), Ca2+ transients, fractional SR Ca2+ release, and SR Ca2+ load were comparable in wild-type (WT) and RyR2(R4496C+/-) myocytes. Ouabain evoked significant increases in diastolic [Ca2+], peak systolic [Ca2+], fractional SR Ca2+ release, and SR Ca2+ content that were quantitatively similar in WT and RyR2(R4496C+/-) myocytes. Ouabain also induced arrhythmogenic events, i.e. spontaneous Ca2+ 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 Ca2+ 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Action Potentials -
- Animals -
- Calcium - metabolism
- Calcium Signaling -
- Catecholamines - metabolism
- Enzyme Inhibitors - pharmacology
- Female -
- Gene Knock-In Techniques -
- Humans -
- Male -
- Mice -
- Mice, Transgenic -
- Microscopy, Confocal -
- Mutation -
- Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism
- Ouabain - pharmacology
- Patch-Clamp Techniques -
- Phosphorylation -
- Ryanodine Receptor Calcium Release Channel - drug effects Ryanodine Receptor Calcium Release Channel - genetics Ryanodine Receptor Calcium Release Channel - metabolism
- Sarcoplasmic Reticulum - drug effects Sarcoplasmic Reticulum - metabolism
- Sodium - metabolism
- Sodium-Potassium-Exchanging ATPase - antagonists and inhibitors Sodium-Potassium-Exchanging ATPase - metabolism
- Tachycardia, Ventricular - genetics Tachycardia, Ventricular - metabolism Tachycardia, Ventricular - prevention and control
- Thiazepines - pharmacology
- Time Factors -
- Find related publications in this database (Keywords)
- Ryanodine receptor
- Ouabain
- Delayed afterdepolarization
- Sodium
- JTV-519