| First Author | Kalyanasundaram A | Year | 2013 |
| Journal | Cardiovasc Res | Volume | 98 |
| Issue | 2 | Pages | 297-306 |
| PubMed ID | 23135969 | Mgi Jnum | J:211451 |
| Mgi Id | MGI:5575463 | Doi | 10.1093/cvr/cvs334 |
| Citation | Kalyanasundaram A, et al. (2013) Up-regulation of sarcoplasmic reticulum Ca(2+) uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2. Cardiovasc Res 98(2):297-306 |
| abstractText | AIMS: 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. METHODS AND RESULTS: We crossbred mice deficient in expression of cardiac calsequestrin (CASQ2) with mice overexpressing the skeletal muscle isoform of SR Ca(2+)ATPase (SERCA1a). The new double-mutant strains displayed early mortality, congestive HF with left ventricular dilated hypertrophy, and decreased ejection fraction. Intact right ventricular muscle preparations from double-mutant mice preserved normal systolic contractile force but were susceptible to spontaneous contractions. Double-mutant cardiomyocytes while preserving normal amplitude of systolic Ca(2+) transients displayed marked disturbances in diastolic Ca(2+) handling in the form of multiple, periodic Ca(2+) waves and wavelets. Dysregulated myocyte Ca(2+) handling and structural and functional cardiac pathology in double-mutant mice were associated with increased rate of apoptotic cell death. Qualitatively similar results were obtained in a hybrid strain created by crossing CASQ2 knockout mice with mice deficient in phospholamban. CONCLUSION: 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. |
