Enhanced ryanodine receptor-mediated calcium leak determines reduced
sarcoplasmic reticulum calcium content in chronic canine heart failure.
Biophys J, 93 (11):
4083--4092 (December 2007)DOI: 10.1529/biophysj.107.114546
Abstract
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.
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