TY - JOUR
T1 - Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice
AU - Schaeffer, Paul J.
AU - DeSantiago, Jaime
AU - Yang, John
AU - Flagg, Thomas P.
AU - Kovacs, Attila
AU - Weinheimer, Carla J.
AU - Courtois, Michael
AU - Leone, Teresa C.
AU - Nichols, Colin G.
AU - Bers, Donald M.
AU - Kelly, Daniel P.
PY - 2009/10
Y1 - 2009/10
N2 - 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.
AB - 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.
KW - Calcium signaling
KW - Cardiac hypertrophy
KW - Cardiac mitochondria
KW - Excitation-contraction coupling
KW - Restrictive cardiomyopathy
UR - http://www.scopus.com/inward/record.url?scp=70349610465&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00152.2009
DO - 10.1152/ajpheart.00152.2009
M3 - Article
C2 - 19700627
AN - SCOPUS:70349610465
SN - 0363-6135
VL - 297
SP - H1263-H1273
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 4
ER -