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Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2009 Oct; Vol. 297 (4), pp. H1263-73. Date of Electronic Publication: 2009 Aug 21. - Publication Year :
- 2009
-
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.
- Subjects :
- Aging metabolism
Animals
Calcineurin genetics
Calcium-Binding Proteins metabolism
Cardiomyopathies genetics
Cardiomyopathies pathology
Cardiomyopathies physiopathology
Cardiotonic Agents administration & dosage
Dobutamine administration & dosage
Fatty Acids metabolism
Genotype
Heart Ventricles metabolism
Heart Ventricles physiopathology
Intracellular Signaling Peptides and Proteins genetics
Male
Mice
Mice, Knockout
Mitochondria, Heart metabolism
Muscle Proteins genetics
Myocardium pathology
Oxidation-Reduction
Phenotype
Phosphorylation
Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
Serine
Sodium-Calcium Exchanger metabolism
Threonine
Ventricular Dysfunction, Left genetics
Ventricular Dysfunction, Left pathology
Ventricular Dysfunction, Left physiopathology
Ventricular Remodeling
Calcineurin deficiency
Calcium Signaling genetics
Cardiomyopathies metabolism
Intracellular Signaling Peptides and Proteins deficiency
Muscle Proteins deficiency
Myocardial Contraction drug effects
Myocardial Contraction genetics
Myocardium metabolism
Ventricular Dysfunction, Left metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 297
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 19700627
- Full Text :
- https://doi.org/10.1152/ajpheart.00152.2009