Circulation Research, Vol 75, 401-409, Copyright © 1994 by American Heart Association

ARTICLES

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

W Luo, IL Grupp, J Harrer, S Ponniah, G Grupp, JJ Duffy, T Doetschman and EG Kranias
Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, OH 45267-0575.

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.

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				D. E. Michele, C. A. Gomez, K. E. Hong, M. V. Westfall, and J. M. Metzger Cardiac Dysfunction in Hypertrophic Cardiomyopathy Mutant Tropomyosin Mice Is Transgene-Dependent, Hypertrophy-Independent, and Improved by {beta}-Blockade Circ. Res., August 9, 2002; 91(3): 255 - 262. [Abstract] [Full Text] [PDF]

				M. Asahi, K. Kurzydlowski, M. Tada, and D. H. MacLennan Sarcolipin Inhibits Polymerization of Phospholamban to Induce Superinhibition of Sarco(endo)plasmic Reticulum Ca2+-ATPases (SERCAs) J. Biol. Chem., July 19, 2002; 277(30): 26725 - 26728. [Abstract] [Full Text] [PDF]

				A. N. Carr, A. G. Schmidt, Y. Suzuki, F. del Monte, Y. Sato, C. Lanner, K. Breeden, S.-L. Jing, P. B. Allen, P. Greengard, et al. Type 1 Phosphatase, a Negative Regulator of Cardiac Function Mol. Cell. Biol., June 15, 2002; 22(12): 4124 - 4135. [Abstract] [Full Text] [PDF]

				M. D. Fischer, J. R. Gorospe, E. Felder, S. Bogdanovich, F. Pedrosa-Domellof, R. S. Ahima, N. A. Rubinstein, E. P. Hoffman, and T. S. Khurana Expression profiling reveals metabolic and structural components of extraocular muscles Physiol Genomics, May 10, 2002; 9(2): 71 - 84. [Abstract] [Full Text] [PDF]

				B. M. Wolska, G. M. Arteaga, J. R. Pena, G. Nowak, R. M. Phillips, S. Sahai, P. P. de Tombe, A. F. Martin, E. G. Kranias, and R. J. Solaro Expression of Slow Skeletal Troponin I in Hearts of Phospholamban Knockout Mice Alters the Relaxant Effect of {beta}-Adrenergic Stimulation Circ. Res., May 3, 2002; 90(8): 882 - 888. [Abstract] [Full Text] [PDF]

				Y. Pi, K. R. Kemnitz, D. Zhang, E. G. Kranias, and J. W. Walker Phosphorylation of Troponin I Controls Cardiac Twitch Dynamics: Evidence From Phosphorylation Site Mutants Expressed on a Troponin I-Null Background in Mice Circ. Res., April 5, 2002; 90(6): 649 - 656. [Abstract] [Full Text] [PDF]

				Y. Kimura and M. Inui Reconstitution of the Cytoplasmic Interaction between Phospholamban and Ca2+-ATPase of Cardiac Sarcoplasmic Reticulum Mol. Pharmacol., March 1, 2002; 61(3): 667 - 673. [Abstract] [Full Text] [PDF]

				F. del Monte, S. E. Harding, G. W. Dec, J. K. Gwathmey, and R. J. Hajjar Targeting Phospholamban by Gene Transfer in Human Heart Failure Circulation, February 26, 2002; 105(8): 904 - 907. [Abstract] [Full Text] [PDF]

				Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes Circ. Res., February 22, 2002; 90(3): 309 - 316. [Abstract] [Full Text] [PDF]

				S. Bartel, B. Hoch, D. Vetter, and E.-G. Krause Expression of Human Angiotensinogen-Renin in Rat: Effects on Transcription and Heart Function Hypertension, February 1, 2002; 39(2): 219 - 223. [Abstract] [Full Text] [PDF]

				H. Kiriazis, Y. Sato, V. J Kadambi, A. G Schmidt, M. J Gerst, B. D Hoit, and E. G Kranias Hypertrophy and functional alterations in hyperdynamic phospholamban-knockout mouse hearts under chronic aortic stenosis Cardiovasc Res, February 1, 2002; 53(2): 372 - 381. [Abstract] [Full Text] [PDF]

				M. J. Lohse and S. Engelhardt Protein Kinase A Transgenes: The Many Faces of cAMP Circ. Res., November 23, 2001; 89(11): 938 - 940. [Full Text] [PDF]

				R. R. Zwaal, K. Van Baelen, J. T. M. Groenen, A. van Geel, V. Rottiers, T. Kaletta, L. Dode, L. Raeymaekers, F. Wuytack, and T. Bogaert The Sarco-Endoplasmic Reticulum Ca2+ ATPase Is Required for Development and Muscle Function in Caenorhabditis elegans J. Biol. Chem., November 16, 2001; 276(47): 43557 - 43563. [Abstract] [Full Text] [PDF]

				R. Shenoy, I. Klein, and K. Ojamaa Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1690 - H1696. [Abstract] [Full Text] [PDF]

				K. Nobe, R. L Sutliff, E. G Kranias, and R. J Paul Phospholamban regulation of bladder contractility: evidence from gene-altered mouse models J. Physiol., September 15, 2001; 535(3): 867 - 878. [Abstract] [Full Text] [PDF]

				N. Satoh, T. Sato, M. Shimada, K. Yamada, and Y. Kitada Lusitropic Effect of MCC-135 Is Associated with Improvement of Sarcoplasmic Reticulum Function in Ventricular Muscles of Rats with Diabetic Cardiomyopathy J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1161 - 1166. [Abstract] [Full Text] [PDF]

				G. C. Wellman, L. F. Santana, A. D. Bonev, and M. T. Nelson Role of phospholamban in the modulation of arterial Ca2+ sparks and Ca2+-activated K+ channels by cAMP Am J Physiol Cell Physiol, September 1, 2001; 281(3): C1029 - C1037. [Abstract] [Full Text] [PDF]

				Y. Zhong, S. Ahmed, I. L. Grupp, and M. A. Matlib Altered SR protein expression associated with contractile dysfunction in diabetic rat hearts Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1137 - H1147. [Abstract] [Full Text] [PDF]