Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice

Schaeffer PJ, DeSantiago J, Yang J, Flagg TP, Kovacs A, Weinheimer CJ, Courtois M, Leone TC, Nichols CG, Bers DM, Kelly DP. Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice. Am J Physiol Heart Circ Physiol 297: H1263-H1273, 2009. First published August 21, 2009; doi: 10.1152/ajpheart.00152.2009.-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.