Effect of metoprolol on sarcoplasmic reticulum Ca2+ leak in a rabbit model of heart failure

Background 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.Methods 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.Results 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.Conclusion 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.