title: Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice.
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.
authors.affiliation: Departments of Medicine, Washington University School of Medicine, Center for Cardiovascular Research, St Louis, Missouri, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Schaeffer
authors.forename: Jaime
authors.initials: J
authors.lastname: Desantiago
authors.forename: John
authors.initials: J
authors.lastname: Yang
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Flagg
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.forename: Michael
authors.initials: M
authors.lastname: Courtois
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000172:deficiency* / Q000235:genetics; D020013:Calcium Signaling / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004280:Dobutamine / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010641:Phenotype; D010766:Phosphorylation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012694:Serine; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013912:Threonine; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling; D000099211:Phospholamban
chemical_list: D019703:Calcineurin; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D004280:Dobutamine; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D012694:Serine; D019831:Sodium-Calcium Exchanger; D013912:Threonine; D000099211:Phospholamban; C511512:DSCR1 protein, mouse; C110374:sodium-calcium exchanger 1; C506947:Atp2a2 protein, mouse
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