Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation.
Phospholamban is the regulator of the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum (SR), and it has been suggested to be an important determinant in the inotropic responses of the heart to beta-adrenergic stimulation. To determine the role of phospholamban in vivo, the gene coding for this protein was targeted in murine embryonic stem cells, and mice deficient in phospholamban were generated. The phospholamban-deficient mice showed no gross developmental abnormalities but exhibited enhanced myocardial performance without changes in heart rate. The time to peak pressure and the time to half-relaxation were significantly shorter in phospholamban-deficient mice compared with their wild-type homozygous littermates as assessed in work-performing mouse heart preparations under identical venous returns, afterloads, and heart rates. The first derivatives of intraventricular pressure (+/- dP/dt) were also significantly elevated, and this was associated with an increase in the affinity of the SR Ca(2+)-ATPase for Ca2+ in the phospholamban-deficient hearts. Baseline levels of these parameters in the phospholamban-deficient hearts were equal to those observed in hearts of wild-type littermates maximally stimulated with the beta-agonist isoproterenol. These findings indicate that phospholamban acts as a critical repressor of basal myocardial contractility and may be the key phosphoprotein in mediating the heart's contractile responses to beta-adrenergic agonists.
Luo
W
W
Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, OH 45267-0575.
Grupp
I L
IL
Harrer
J
J
Ponniah
S
S
Grupp
G
G
Duffy
J J
JJ
Doetschman
T
T
Kranias
E G
EG
D000818:Animals; D001755:Blastocyst / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D003001:Cloning, Molecular; D004622:Embryo, Mammalian; D005260:Female; D017353:Gene Deletion; D015698:Genomic Library; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D011555:Pseudopregnancy; D015183:Restriction Mapping; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D000099211:Phospholamban