Altered intracellular Ca2+ regulation in chronic rat heart failure

Altered intracellular Ca2+ handling by the sarcoplasmic reticulum (SR) plays a crucial role in the pathogenesis of heart failure (HF). Despite extensive effort, the underlying causes of abnormal SR Ca2+ handling in HF have not been clarified. To determine whether the diastolic SR Ca2+ leak along with reduced Ca2+ reuptake is required for decreased contractility, we investigated the cytosolic Ca2+ transients and SR Ca2+ content and assessed the expression of ryanodine receptor (RyR2), FK506 binding protein (FKBP12.6), SR-Ca2+ ATPase (SERCA2a), and L-type Ca2+ channel (LTCC) using an SD-rat model of chronic HF. We found that the cytosolic Ca2+ transients were markedly reduced in amplitude in HF myocytes (Delta F/F (0) = 12.3 +/- A 0.8) compared with control myocytes (Delta F/F (0) = 17.7 +/- A 1.2, P < 0.01), changes paralleled by a significant reduction in the SR Ca2+ content (HF: Delta F/F (0) = 12.4 +/- A 1.1, control: Delta F/F (0) = 32.4 +/- A 1.9, P < 0.01). Moreover, we demonstrated that the expression of FKBP12.6 associated with RyR2, SERCA2a, and LTCC was significantly reduced in rat HF. These results provide evidence for phosphorylation-induced detachment of FKBP12.6 from RyRs and down-regulation of SERCA2a and LTCC in HF. We conclude that diastolic SR Ca2+ leak (due to dissociation of FKBP12.6 from RyR2) along with reduced SR Ca2+ uptake (due to down-regulation of SERCA2a) and defective E-C coupling (due to down-regulation of LTCC) could contribute to HF.