Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation - PubMed (original) (raw)
Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation
W Luo et al. Circ Res. 1994 Sep.
Abstract
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.
Comment in
- Ablating a cardiac protein: causality at last.
James J, Robbins J. James J, et al. Circ Res. 2013 May 24;112(11):1415-9. doi: 10.1161/CIRCRESAHA.113.301425. Circ Res. 2013. PMID: 23704216 No abstract available.
Similar articles
- Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice.
Kadambi VJ, Ponniah S, Harrer JM, Hoit BD, Dorn GW 2nd, Walsh RA, Kranias EG. Kadambi VJ, et al. J Clin Invest. 1996 Jan 15;97(2):533-9. doi: 10.1172/JCI118446. J Clin Invest. 1996. PMID: 8567978 Free PMC article. - Targeted overexpression of phospholamban to mouse atrium depresses Ca2+ transport and contractility.
Neumann J, Boknik P, DePaoli-Roach AA, Field LJ, Rockman HA, Kobayashi YM, Kelley JS, Jones LR. Neumann J, et al. J Mol Cell Cardiol. 1998 Oct;30(10):1991-2002. doi: 10.1006/jmcc.1998.0760. J Mol Cell Cardiol. 1998. PMID: 9799653 - The effect of isoproterenol on phospholamban-deficient mouse hearts with altered thyroid conditions.
Brittsan AG, Kiss E, Edes I, Grupp IL, Grupp G, Kranias EG. Brittsan AG, et al. J Mol Cell Cardiol. 1999 Sep;31(9):1725-37. doi: 10.1006/jmcc.1999.1010. J Mol Cell Cardiol. 1999. PMID: 10471356 - Phospholamban and cardiac contractile function.
Brittsan AG, Kranias EG. Brittsan AG, et al. J Mol Cell Cardiol. 2000 Dec;32(12):2131-9. doi: 10.1006/jmcc.2000.1270. J Mol Cell Cardiol. 2000. PMID: 11112989 Review. No abstract available. - Phospholamban: a promising therapeutic target in heart failure?
Schmidt AG, Edes I, Kranias EG. Schmidt AG, et al. Cardiovasc Drugs Ther. 2001 Sep;15(5):387-96. doi: 10.1023/a:1013381204658. Cardiovasc Drugs Ther. 2001. PMID: 11855657 Review.
Cited by
- A novel role for phospholamban in the thalamic reticular nucleus.
Klocke B, Britzolaki A, Saurine J, Ott H, Krone K, Bahamonde K, Thelen C, Tzimas C, Sanoudou D, Kranias EG, Pitychoutis PM. Klocke B, et al. Sci Rep. 2024 Mar 16;14(1):6376. doi: 10.1038/s41598-024-56447-x. Sci Rep. 2024. PMID: 38493225 Free PMC article. - Myofilament-based physiological regulatory compensation preserves diastolic function in failing hearts with severe Ca2+ handling deficits.
Heinis FI, Thompson BR, Gulati R, Wheelwright M, Metzger JM. Heinis FI, et al. JCI Insight. 2024 Feb 8;9(6):e163334. doi: 10.1172/jci.insight.163334. JCI Insight. 2024. PMID: 38329806 Free PMC article. - Polyarginine Cell-Penetrating Peptides Bind and Inhibit SERCA2.
Lunde PK, Manfra O, Støle TP, Lunde M, Martinsen M, Carlson CR, Louch WE. Lunde PK, et al. Cells. 2023 Sep 26;12(19):2358. doi: 10.3390/cells12192358. Cells. 2023. PMID: 37830576 Free PMC article. - 1821-2021: Contributions of physicians and researchers of Greek descent in the advancement of clinical and experimental cardiology and cardiac surgery.
Gerontas A, Avgerinos D, Charitakis K, Maragou H, Drosatos K. Gerontas A, et al. Front Cardiovasc Med. 2023 Aug 4;10:1231762. doi: 10.3389/fcvm.2023.1231762. eCollection 2023. Front Cardiovasc Med. 2023. PMID: 37600045 Free PMC article. Review. - Microproteins: Overlooked regulators of physiology and disease.
Hassel KR, Brito-Estrada O, Makarewich CA. Hassel KR, et al. iScience. 2023 Apr 29;26(6):106781. doi: 10.1016/j.isci.2023.106781. eCollection 2023 Jun 16. iScience. 2023. PMID: 37213226 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous