Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation
| Autor: | John J. Duffy, Ingrid L. Grupp, Judy M. Harrer, Thomas Doetschman, Wusheng Luo, Sathivel Ponniah, Gunter Grupp, Evangelia G. Kranias |
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| Rok vydání: | 1994 |
| Předmět: |
Male
Inotrope Agonist medicine.medical_specialty Cardiac output Physiology medicine.drug_class Blotting Western Restriction Mapping Stimulation Calcium-Transporting ATPases In Vitro Techniques Biology Contractility Mice Internal medicine Heart rate medicine Animals Cardiac Output Cloning Molecular Pseudopregnancy Genomic Library Mice Inbred C3H Myocardium Stem Cells Calcium-Binding Proteins Isoproterenol Heart Embryo Mammalian musculoskeletal system Myocardial Contraction Phospholamban Mice Inbred C57BL Sarcolipin Sarcoplasmic Reticulum Blastocyst Endocrinology cardiovascular system Calcium Female Cardiology and Cardiovascular Medicine Gene Deletion circulatory and respiratory physiology |
| Zdroj: | Circulation Research. 75:401-409 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/01.res.75.3.401 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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