title: Up-regulation of sarcoplasmic reticulum Ca(2+) uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, 505 Davis Heart and Lung Research Institute, The Ohio State University, 473 W 12th Ave, Columbus, OH 43210, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalyanasundaram
authors.forename: Véronique A
authors.initials: VA
authors.lastname: Lacombe
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.forename: Lucia
authors.initials: L
authors.lastname: Brunello
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Bjørn C
authors.initials: BC
authors.lastname: Knollmann
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
authors.forename: Sandor
authors.initials: S
authors.lastname: Gyørke
mesh_terms: D000818:Animals; D017209:Apoptosis; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002118:Calcium / Q000378:metabolism*; D002155:Calsequestrin / Q000172:deficiency / Q000502:physiology*; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D003971:Diastole; D006333:Heart Failure / Q000209:etiology; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D015854:Up-Regulation; D020257:Ventricular Remodeling
chemical_list: C506944:Atp2a1 protein, mouse; D002155:Calsequestrin; C514388:casq2 protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium