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 journalArticle

25 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 (US)
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

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Schaeffer, P. J., DeSantiago, J., Yang, J., Flagg, T. P., Kovacs, A., Weinheimer, C. J., Courtois, M., Leone, T. C., Nichols, C. G., Bers, D. M., & Kelly, D. P. (2009). Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice. American Journal of Physiology - Heart and Circulatory Physiology, 297(4). https://doi.org/10.1152/ajpheart.00152.2009