Enhanced ryanodine receptor-mediated calcium leak determines reduced sarcoplasmic reticulum calcium content in chronic canine heart failure.
In this study, we investigated the role of elevated sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptors (RyR2s) in heart failure (HF)-related abnormalities of intracellular Ca(2+) handling, using a canine model of chronic HF. The cytosolic Ca(2+) transients were reduced in amplitude and slowed in duration in HF myocytes compared with control, changes paralleled by a dramatic reduction in the total SR Ca(2+) content. Direct measurements of [Ca(2+)](SR) in both intact and permeabilized cardiac myocytes demonstrated that SR luminal [Ca(2+)] is markedly lowered in HF, suggesting that alterations in Ca(2+) transport rather than fractional SR volume reduction accounts for the diminished Ca(2+) release capacity of SR in HF. SR Ca(2+) ATPase (SERCA2)-mediated SR Ca(2+) uptake rate was not significantly altered, and Na(+)/Ca(2+) exchange activity was accelerated in HF myocytes. At the same time, SR Ca(2+) leak, measured directly as a loss of [Ca(2+)](SR) after inhibition of SERCA2 by thapsigargin, was markedly enhanced in HF myocytes. Moreover, the reduced [Ca(2+)](SR) in HF myocytes could be nearly completely restored by the RyR2 channel blocker ruthenium red. The effects of HF on cytosolic and SR luminal Ca(2+) signals could be reasonably well mimicked by the RyR2 channel agonist caffeine. Taken together, these results suggest that RyR2-mediated SR Ca(2+) leak is a major factor in the abnormal intracellular Ca(2+) handling that critically contributes to the reduced SR Ca(2+) content of failing cardiomyocytes.
Belevych
Andriy
A
Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, Ohio State University Medical Center, Columbus, Ohio 43210, USA.
Kubalova
Zuzana
Z
Terentyev
Dmitry
D
Hamlin
Robert L
RL
Carnes
Cynthia A
CA
Györke
Sandor
S
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002303:Cardiac Output, Low / Q000378:metabolism*; D002478:Cells, Cultured; D002908:Chronic Disease; D004285:Dogs; D015640:Ion Channel Gating; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*