Effect of metoprolol on sarcoplasmic reticulum Ca2+ leak in a rabbit model of heart failure / 中华医学杂志(英文版)
Chinese Medical Journal
;
(24): 815-822, 2012.
Article
in English
| WPRIM
| ID: wpr-262520
ABSTRACT
<p><b>BACKGROUND</b>Studies have shown that β-blockers can improve cardiac performance in heart failure (HF) by reversing protein kinase A (PKA)-mediated sarcoplasmic reticulum (SR) Ca2+ leak. However, it is being strongly questioned as to whether the PKA-mediated ryanodine receptor (RyR2) hyper-phosphorylation is a critical regulator of SR Ca2+ leak. In this study, we used a rabbit HF model to investigate whether β-blockers affect SR Ca2+ leak by other potential mechanisms.</p><p><b>METHODS</b>New Zealand white rabbits were randomly divided in three groups (n=7 in each group) normal group, metoprolol-untreated group and metoprolol-treated group. Cardiac function was determined by echocardiography and hemodynamic assays. The SR Ca2+ leak was measured by a calcium-imaging device, and the expression and activities of related proteins were evaluated by Western blotting and auto-phosphorylation.</p><p><b>RESULTS</b>In the metoprolol-untreated group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca2+ leak, reduced associated amount of FK506 binding protein 12.6 (FKBP12.6), increased expression and activity of PKA and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and increased phosphorylated RyR2 phosphorylation sites (with unchanged RyR2-P2030). In the treated group, there was partly increased ventricular cavity size with preserved systolic function, but no prominent Ca2+ leak, with unchanged expression and activity of PKA, CaMKII and their RyR2 phosphorylation sites.</p><p><b>CONCLUSION</b>Chronic administration of metoprolol prevented the SR Ca2+ leak by restoring not only PKA-dependent but also CaMKII-dependent hyper-phosphorylation of RyR2, which may be one of the potential mechanisms by which β-blockers improve cardiac function and reduce the incidence of fatal arrhythmia in HF.</p>
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Sarcoplasmic Reticulum
/
Echocardiography
/
Calcium
/
Cyclic AMP-Dependent Protein Kinases
/
Therapeutic Uses
/
Drug Therapy
/
Calcium-Calmodulin-Dependent Protein Kinase Type 2
/
Heart Failure
/
Hemodynamics
/
Metabolism
Type of study:
Prognostic study
Limits:
Animals
Language:
English
Journal:
Chinese Medical Journal
Year:
2012
Type:
Article
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