Cardiovascular research
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Cardiovascular research · May 2013
Up-regulation of sarcoplasmic reticulum Ca(2+) uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2.
Although aberrant Ca(2+) release (i.e. Ca(2+) 'leak') from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptors (RyR2) is linked to heart failure (HF), it remains unknown whether and under what conditions SR-derived Ca(2+) can actually cause HF. We tested the hypothesis that combining dysregulated RyR2 function with facilitated Ca(2+) uptake into SR will exacerbate abnormal SR Ca(2+) release and induce HF. We also examined the mechanisms for these alterations. ⋯ We demonstrate that enhanced SR Ca(2+) uptake combined with dysregulated RyR2s results in sustained diastolic Ca(2+) release causing apoptosis, dilated cardiomyopathy, and early mortality. Our data also suggest that up-regulation of SERCA activity must be advocated with caution as a therapy for HF in the context of abnormal RyR2 function.