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

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 (Ppp3rl) gene ([csCnbl.sup.-/-] mice) was characterized, [csCnbl.sup.-/-] 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 [csCnbl.sup.-/-] 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 mticulum Ca-ATPase 2a (Atp2a2) and phospholamban were normal, but phospholamban phosphorylation was markedly reduced at [Ser.sup.16] and [Thr.sup.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. calcium signaling; restrictive cardiomyopathy; cardiac hypertrophy; excitation-contraction coupling; cardiac mitochondria doi: 10.1152/ajpheart.00152.2009