Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Dybkova, N; Sedej, S; Napolitano, C; Neef, S; Rokita, AG; Hünlich, M; Brown, JH; Kockskämper, J; Priori, SG; Pieske, B; Maier, LS.
Overexpression of CaMKIIδc in RyR2R4496C+/- knock-in mice leads to altered intracellular Ca2+ handling and increased mortality.
J Am Coll Cardiol. 2011; 57(4):469-479
Doi: 10.1016/j.jacc.2010.08.639
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Pieske Burkert Mathias
- Sedej Simon
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- Objectives We investigated whether increased Ca2+/calmodulin-dependent kinase II (CaMKII) activity aggravates defective excitation-contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2). Background RyR2 dysfunction is associated with arrhythmic events in inherited and acquired cardiac disease. Methods CaMKII delta c transgenic mice were crossbred with RyR2(R4496C+/-) knock-in mice. Results Heart weight-to-body weight ratio in CaMKII delta c/RyR2(R4496C) and CaMKII delta c mice was similarly increased approximately 3-fold versus wild-type mice (p < 0.05). Echocardiographic data showed comparable cardiac dilation and impaired contractility in CaMKII delta c/RyR2(R4496C) and CaMKII delta c mice. Sarcoplasmic reticulum Ca2+ content in isolated myocytes was decreased to a similar extent in CaMKII delta c/RyR2(R4496C) and CaMKII delta c mice. However, relaxation parameters and Ca2+ decay at 1 Hz were prolonged significantly in CaMKII delta c mice versus CaMKII delta c/RyR2(R4496C) mice. Sarcoplasmic reticulum Ca2+ spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca2+ leak in CaMKII delta c/RyR2(R4496C) versus CaMKII delta c myocytes (p < 0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKII delta c/RyR2(R4496C) versus CaMKII delta c mice. Increased arrhythmias in vivo (67% vs. 25%; p < 0.05) may explain the increased mortality in CaMKII delta c/RyR2(R4496C) mice, which died prematurely with only 30% alive (vs. 60% for CaMKII delta c, p < 0.05) after 14 weeks. Conclusions CaMKII delta c overexpression in RyR2(R4496C+/-) knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor. (J Am Coll Cardiol 2011; 57: 469-79) (C) 2011 by the American College of Cardiology Foundation
- Find related publications in this database (using NLM MeSH Indexing)
- Analysis of Variance -
- Animals -
- Arrhythmias, Cardiac - genetics
- Calcium - metabolism
- Calcium Signaling -
- Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics
- Cardiomegaly - genetics
- Chi-Square Distribution -
- Disease Models, Animal -
- Echocardiography -
- Excitation Contraction Coupling - genetics
- Gene Expression Regulation -
- Mice -
- Mice, Knockout -
- Mice, Transgenic -
- Myocardial Contraction - physiology
- Phosphorylation -
- Random Allocation -
- Ryanodine Receptor Calcium Release Channel - metabolism
- Find related publications in this database (Keywords)
- arrhythmias
- CaMKII delta c overexpression
- intracellular Ca2+ handling
- mutated ryanodine receptors
- sarcoplasmic reticulum Ca2+ leak