Differences in Sarcoplasmic Reticulum Ca(superscript 2+) Leak Characteristics between Systolic and Diastolic Heart Failure Rabbit Models

Abstract

Diastolic heart failure (DHF) and systolic heart failure (SHF) are two clinical subsets of chronic heart failure (CHF). Sarcoplasmic reticulum (SR) Ca²⁺ leak has been measured in SHF and might contribute to contractile dysfunction and arrhythmogenesis. However, no study has investigated a similar phenomenon in DHF. Thus, we established DHF and SHF rabbit models and compared the differences in Ca²⁺ leak between these models. New Zealand white rabbits were randomly divided into three groups (n = 8 in each group): sham operation (SO) group, DHF group and SHF group. Cardiac functions were determined by echocardiography and hemodynamic assays. The SR Ca²⁺ leak was measured with a calcium-imaging device and the expression and activities of related proteins were evaluated with Western blots and autophosphorylation. In the DHF group, there was significantly increased ventricular wall thickness and stiffness, reduced diastolic function, and total amount of FK506 binding protein 12.6 (FKBP12.6), increased expression and activity of protein kinase A (PKA) and phosphorylation site (P2809) in the ryanodine receptor (RyR2), but no prominent Ca²⁺ leak. In the SHF group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca²⁺ leak, reduced total amount of FKBP12.6 and FKBP12.6-RyR2 association, increased expression and activity of PKA and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and their RyR2 phosphorylation sites with unchanged P2030. Our results suggest that a prominent SR Ca²⁺ leak was not observed in the DHF model, which may provide a new idea for the reasons in preserved systolic function, and CaMKII possibly plays a more important role in SR Ca²⁺ leak.