Abstract
To define the necessity of calcineurin (Cn) signaling for cardiac maturation and function, the postnatal phenotype of mice with cardiac-specific targeted ablation of the Cn B1 regulatory subunit (Ppp3r1) gene (csCnb1(-/-) mice) was characterized. csCnb1(-/-) mice develop a lethal cardiomyopathy, characterized by impaired postnatal growth of the heart and combined systolic and diastolic relaxation abnormalities, despite a lack of structural derangements. Notably, the csCnb1(-/-) hearts did not exhibit diastolic dilatation, despite the severe functional phenotype. Myocytes isolated from the mutant mice exhibited reduced rates of contraction/relaxation and abnormalities in calcium transients, consistent with altered sarcoplasmic reticulum loading. Levels of sarco(endo) plasmic reticulum Ca-ATPase 2a (Atp2a2) and phospholamban were normal, but phospholamban phosphorylation was markedly reduced at Ser(16) and Thr(17). In addition, levels of the Na/Ca exchanger (Slc8a1) were modestly reduced. These results define a novel mouse model of cardiac-specific Cn deficiency and demonstrate novel links between Cn signaling, postnatal growth of the heart, pathological ventricular remodeling, and excitation-contraction coupling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aging / metabolism
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Animals
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Calcineurin / deficiency*
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Calcineurin / genetics
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Calcium Signaling* / genetics
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Calcium-Binding Proteins / metabolism
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Cardiomyopathies / genetics
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Cardiomyopathies / metabolism*
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Cardiomyopathies / pathology
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Cardiomyopathies / physiopathology
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Cardiotonic Agents / administration & dosage
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Dobutamine / administration & dosage
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Fatty Acids / metabolism
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Genotype
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Heart Ventricles / metabolism
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Heart Ventricles / physiopathology
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Intracellular Signaling Peptides and Proteins / deficiency*
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Intracellular Signaling Peptides and Proteins / genetics
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Male
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Mice
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Mice, Knockout
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Mitochondria, Heart / metabolism
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Muscle Proteins / deficiency*
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Muscle Proteins / genetics
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Myocardial Contraction* / drug effects
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Myocardial Contraction* / genetics
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Myocardium / metabolism*
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Myocardium / pathology
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Oxidation-Reduction
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Phenotype
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Phosphorylation
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
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Serine
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Sodium-Calcium Exchanger / metabolism
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Threonine
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Ventricular Dysfunction, Left / genetics
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Ventricular Dysfunction, Left / metabolism*
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Ventricular Dysfunction, Left / pathology
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Ventricular Dysfunction, Left / physiopathology
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Ventricular Remodeling
Substances
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Calcium-Binding Proteins
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Cardiotonic Agents
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DSCR1 protein, mouse
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Fatty Acids
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Intracellular Signaling Peptides and Proteins
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Muscle Proteins
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Sodium-Calcium Exchanger
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phospholamban
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sodium-calcium exchanger 1
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Threonine
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Dobutamine
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Serine
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Calcineurin
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Atp2a2 protein, mouse