Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of β-agonist stimulation

W. Luo, I. L. Grupp, J. Harrer, S. Ponniah, G. Grupp, J. J. Duffy, T. Doetschman, E. G. Kranias

Research output: Contribution to journalArticle

597 Scopus citations

Abstract

Phospholamban is the regulator of the Ca2+-ATPase in cardiac sarcoplasmic reticulum (SR), and it has been suggested to be an important determinant in the inotropic responses of the heart to β-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 Ca2+-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 β-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 β-adrenergic agonists.

Original languageEnglish (US)
Pages (from-to)401-409
Number of pages9
JournalCirculation research
Volume75
Issue number3
DOIs
StatePublished - Jan 1 1994
Externally publishedYes

Keywords

  • cardiac contractility
  • gene targeting
  • phospholamban
  • sarcoplasmic reticulum
  • β-agonists

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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