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 (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.
Schaeffer
Paul J
PJ
Departments of Medicine, Washington University School of Medicine, Center for Cardiovascular Research, St Louis, Missouri, USA.
Desantiago
Jaime
J
Yang
John
J
Flagg
Thomas P
TP
Kovacs
Attila
A
Weinheimer
Carla J
CJ
Courtois
Michael
M
Leone
Teresa C
TC
Nichols
Colin G
CG
Bers
Donald M
DM
Kelly
Daniel P
DP
D000375:Aging / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000172:deficiency* / Q000235:genetics; D020013:Calcium Signaling / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004280:Dobutamine / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010641:Phenotype; D010766:Phosphorylation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012694:Serine; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013912:Threonine; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling; D000099211:Phospholamban
D019703:Calcineurin; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D004280:Dobutamine; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D012694:Serine; D019831:Sodium-Calcium Exchanger; D013912:Threonine; D000099211:Phospholamban; C511512:DSCR1 protein, mouse; C110374:sodium-calcium exchanger 1; C506947:Atp2a2 protein, mouse
Circ Res. 2005 Dec 9;97(12):1314-22
16269653
Circ Res. 2004 Sep 17;95(6):604-11
15308581
Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1361-9
14656703
J Clin Invest. 1997 Jul 1;100(1):169-79
9202069
J Physiol. 1992;453:591-608
1464847
J Clin Invest. 1996 Jan 15;97(2):533-9
8567978
J Biol Chem. 2004 Jun 18;279(25):26192-200
15082723
Biochem Biophys Res Commun. 2003 Nov 28;311(4):1181-93
14623304
Circ Res. 1994 Sep;75(3):401-9
8062415
J Biol Chem. 2007 Mar 30;282(13):10068-10078
17289669
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3322-7
11248077
Circ Res. 2003 Sep 19;93(6):487-90
14500331
Genes Dev. 2003 Sep 15;17(18):2205-32
12975316
Circ Res. 2004 Jan 9;94(1):110-8
14656927
Physiol Rev. 2000 Oct;80(4):1483-521
11015619
Cardiovasc Res. 2005 Dec 1;68(3):366-75
16226237
Circ Res. 2000 Oct 27;87(9):731-8
11055975
J Clin Invest. 2000 Oct;106(7):847-56
11018072
Biophys J. 2000 Jan;78(1):334-43
10620297
Circ Res. 1999 Apr 2;84(6):735-40
10189362
Cell. 2001 Jun 29;105(7):863-75
11439183
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3328-33
11248078
J Biol Chem. 2003 Sep 26;278(39):36981-4
12881512
Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
16936699
Immunity. 2004 Mar;20(3):255-66
15030770
J Biol Chem. 2004 Sep 17;279(38):39593-603
15262994
Nat Rev Mol Cell Biol. 2003 Jul;4(7):566-77
12838339
J Exp Med. 1996 Feb 1;183(2):413-20
8627154
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4586-91
11904392
J Biol Chem. 2004 May 14;279(20):21383-93
15020584
Cardiovasc Res. 2002 Apr;54(1):105-16
12062367
Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H61-70
16772527
Mol Cell Biol. 2005 Feb;25(3):865-78
15657416
Circulation. 2000 May 23;101(20):2431-7
10821822
Mol Cell Biol. 2003 Jun;23(12):4331-43
12773574
Cell. 2000 Jun 23;101(7):689-92
10892739
J Biol Chem. 2007 Dec 14;282(50):36642-51
17932032
Cell. 1999 Mar 5;96(5):611-4
10089876
J Mol Cell Cardiol. 2002 Mar;34(3):321-34
11945024
Circ Res. 2008 Feb 1;102(2):242-9
18007024
Cell. 1998 Apr 17;93(2):215-28
9568714
J Biol Chem. 1985 Jun 25;260(12):7757-64
3997893
Am J Physiol. 1998 Apr;274(4):H1335-47
9575939
J Biol Chem. 1994 Oct 7;269(40):25073-7
7929194
Pflugers Arch. 2003 Nov;447(2):150-7
14530977
J Clin Invest. 1999 Sep;104(5):567-76
10487771