Altered intracellular Ca2+ regulation in chronic rat heart failure.
intracellular Ca(2+) 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 Ca(2+) handling in HF have not been clarified. To determine whether the diastolic SR Ca(2+) leak along with reduced Ca(2+) reuptake is required for decreased contractility, we investigated the cytosolic Ca(2+) transients and SR Ca(2+) content and assessed the expression of ryanodine receptor (RyR2), FK506 binding protein (FKBP12.6), SR-Ca(2+) ATPase (SERCA2a), and L-type Ca(2+) channel (LTCC) using an SD-rat model of chronic HF. We found that the cytosolic Ca(2+) transients were markedly reduced in amplitude in HF myocytes (DeltaF/F(0) = 12.3 +/- 0.8) compared with control myocytes (DeltaF/F(0) = 17.7 +/- 1.2, P < 0.01), changes paralleled by a significant reduction in the SR Ca(2+) content (HF: DeltaF/F(0) = 12.4 +/- 1.1, control: DeltaF/F(0) = 32.4 +/- 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 Ca(2+) leak (due to dissociation of FKBP12.6 from RyR2) along with reduced SR Ca(2+) uptake (due to down-regulation of SERCA2a) and defective E-C coupling (due to down-regulation of LTCC) could contribute to HF.
Hu
Shu-Ting
ST
Department of Biophysics, Second Military Medical University, No. 800 Xiangyin Road, 200433, Shanghai, People's Republic of China.
Shen
Ya-Feng
YF
Liu
Guan-Sheng
GS
Lei
Chang-Hai
CH
Tang
Ying
Y
Wang
Jian-Fei
JF
Yang
Yong-Ji
YJ
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D002908:Chronic Disease; D006333:Heart Failure / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D002118:Calcium