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

Paul J. Schaeffer, Jaime DeSantiago, John Yang, Thomas P. Flagg, Attila Kovacs, Carla J. Weinheimer, Michael Courtois, Teresa C. Leone, Colin G. Nichols, Donald M. Bers, Daniel P. Kelly

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 Ser16 and Thr17. 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.

Original languageEnglish
Pages (from-to)H1263-H1273
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number4
DOIs
StatePublished - Oct 2009

Keywords

  • Calcium signaling
  • Cardiac hypertrophy
  • Cardiac mitochondria
  • Excitation-contraction coupling
  • Restrictive cardiomyopathy

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