© 1996 American Heart Association, Inc.
Articles |
Compensatory Mechanisms Associated With the Hyperdynamic Function of Phospholamban-Deficient Mouse Hearts
the Departments of Pharmacology and Cell Biophysics (G.C., W.L., J.P.S., C.T., M.A.M., I.L.G., E.G.K.) and Pathology & Laboratory Medicine (G.P.B.), University of Cincinnati (Ohio); the Center for Anesthesiology Research (W.E.S., C.S.M.), Cleveland (Ohio) Clinic Foundation; and the NMR Laboratory for Physiological Chemistry (M.S., K.W.S., J.S.I.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Evangelia G. Kranias, PhD, Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, PO Box 670575, Cincinnati, OH 45267-0575.
Phospholamban ablation is associated with significant increases in the sarcoplasmic reticulum Ca2+-ATPase activity and the basal cardiac contractile parameters. To determine whether the observed phenotype is due to loss of phospholamban alone or to accompanying compensatory mechanisms, hearts from phospholamban-deficient and age-matched wild-type mice were characterized in parallel. There were no morphological alterations detected at the light microscope level. Assessment of the protein levels of the cardiac sarcoplasmic reticulum Ca2+-ATPase, calsequestrin, myosin, actin, troponin I, and troponin T revealed no significant differences between phospholamban-deficient and wild-type hearts. However, the ryanodine receptor protein levels were significantly decreased (25%) upon ablation of phospholamban, probably in an attempt to regulate the release of Ca2+ from the sarcoplasmic reticulum, which had a significantly higher diastolic Ca2+ content in phospholamban-deficient compared with wild-type hearts (16.0±2.2 versus 8.6±1.0 mmol Ca2+/kg dry wt, respectively). The increases in Ca2+ content were specific to junctional sarcoplasmic reticulum stores, as there were no alterations in the Ca2+ content of the mitochondria or A band. Assessment of ATP levels revealed no alterations, although oxygen consumption increased (1.6-fold) to meet the increased ATP utilization in the hyperdynamic phospholamban-deficient hearts. The increases in oxygen consumption were associated with increases (2.2-fold) in the active fraction of the mitochondrial pyruvate dehydrogenase, suggesting increased tricarboxylic acid cycle turnover and ATP synthesis. 31P nuclear magnetic resonance studies demonstrated decreases in phosphocreatine levels and increases in ADP and AMP levels in phospholamban-deficient compared with wild-type hearts. However, the creatine kinase activity and the creatine kinase reaction velocity were not different between phospholamban-deficient and wild-type hearts. These findings indicate that ablation of phospholamban is associated with downregulation of the ryanodine receptor to compensate for the increased Ca2+ content in the sarcoplasmic reticulum store and metabolic adaptations to establish a new energetic steady state to meet the increased ATP demand in the hyperdynamic phospholamban-deficient hearts.
Key Words: phospholamban • sarcoplasmic reticulum • Ca2+ stores • nuclear magnetic resonance • mitochondrial enzymes
This article has been cited by other articles:
 |
|
 |
|
  M. Gnecchi, H. He, L. G. Melo, N. Noiseaux, F. Morello, R. A. de Boer, L. Zhang, R. E. Pratt, V. J. Dzau, and J. S. Ingwall Early Beneficial Effects of Bone Marrow-Derived Mesenchymal Stem Cells Overexpressing Akt on Cardiac Metabolism After Myocardial Infarction Stem Cells, April 1, 2009; 27(4): 971 - 979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Vafiadaki, D. A. Arvanitis, S. N. Pagakis, V. Papalouka, D. Sanoudou, A. Kontrogianni-Konstantopoulos, and E. G. Kranias The Anti-apoptotic Protein HAX-1 Interacts with SERCA2 and Regulates Its Protein Levels to Promote Cell Survival Mol. Biol. Cell, January 1, 2009; 20(1): 306 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Pinz, S. E. Ostroy, K. Hoyer, H. Osinska, J. Robbins, J. D. Molkentin, and J. S. Ingwall Calcineurin-induced energy wasting in a transgenic mouse model of heart failure Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1459 - H1466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Belke, E. Swanson, J. Suarez, B. T. Scott, A. E. Stenbit, and W. H. Dillmann Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1755 - H1763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mattiazzi, C. Mundina-Weilenmann, C. Guoxiang, L. Vittone, and E. Kranias Role of phospholamban phosphorylation on Thr17 in cardiac physiological and pathological conditions Cardiovasc Res, December 1, 2005; 68(3): 366 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M Janczewski, M. Zahid, B. H Lemster, C. S Frye, G. Gibson, Y. Higuchi, E. G Kranias, A. M Feldman, and C. F McTiernan Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model Cardiovasc Res, June 1, 2004; 62(3): 468 - 480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R Pena and B. M Wolska Troponin I phosphorylation plays an important role in the relaxant effect of {beta}-adrenergic stimulation in mouse hearts Cardiovasc Res, March 1, 2004; 61(4): 756 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. R. Cross, E. G. Kranias, E. Murphy, and C. Steenbergen Ablation of PLB exacerbates ischemic injury to a lesser extent in female than male mice: protective role of NO Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H683 - H690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhao, K. F Frank, G. Chu, M. J Gerst, A. G Schmidt, Y. Ji, M. Periasamy, and E. G Kranias Combined phospholamban ablation and SERCA1a overexpression result in a new hyperdynamic cardiac state Cardiovasc Res, January 1, 2003; 57(1): 71 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Tupling, M. Asahi, and D. H. MacLennan Sarcolipin Overexpression in Rat Slow Twitch Muscle Inhibits Sarcoplasmic Reticulum Ca2+ Uptake and Impairs Contractile Function J. Biol. Chem., November 15, 2002; 277(47): 44740 - 44746. [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]
|
|
|
|
 |
|
 S.-H. Jo, V. Leblais, P. H. Wang, M. T. Crow, and R.-P. Xiao Phosphatidylinositol 3-Kinase Functionally Compartmentalizes the Concurrent Gs Signaling During {beta}2-Adrenergic Stimulation Circ. Res., July 12, 2002; 91(1): 46 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. del Monte, E. Williams, D. Lebeche, U. Schmidt, A. Rosenzweig, J. K. Gwathmey, E. D. Lewandowski, and R. J. Hajjar Improvement in Survival and Cardiac Metabolism After Gene Transfer of Sarcoplasmic Reticulum Ca2+-ATPase in a Rat Model of Heart Failure Circulation, September 18, 2001; 104(12): 1424 - 1429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E Hebert Signalling in cardiac disease: the molecular deficit at the heart of the problem Cardiovasc Res, April 1, 2001; 50(1): 7 - 9. [Full Text] [PDF]
|
|
|
|
|
|
J. Zhai, A. G. Schmidt, B. D. Hoit, Y. Kimura, D. H. MacLennan, and E. G. Kranias Cardiac-specific Overexpression of a Superinhibitory Pentameric Phospholamban Mutant Enhances Inhibition of Cardiac Function in Vivo J. Biol. Chem., March 31, 2000; 275(14): 10538 - 10544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Hoit, V. J. Kadambi, D. A. Tramuta, N. Ball, E. G. Kranias, and R. A. Walsh Influence of sarcoplasmic reticulum calcium loading on mechanical and relaxation restitution Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H958 - H963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Herzig and J. Neumann Effects of Serine/Threonine Protein Phosphatases on Ion Channels in Excitable Membranes Physiol Rev, January 1, 2000; 80(1): 173 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U Ravens and D Dobrev Regulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban in the failing and nonfailing heart Cardiovasc Res, January 1, 2000; 45(1): 245 - 252. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lalli, S. Shimizu, R. L. Sutliff, E. G. Kranias, and R. J. Paul [Ca2+]i homeostasis and cyclic nucleotide relaxation in aorta of phospholamban-deficient mice Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H963 - H970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. J. Kadambi, N. Ball, E. G. Kranias, R. A. Walsh, and B. D. Hoit Modulation of force-frequency relation by phospholamban in genetically engineered mice Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2245 - H2250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Chen, R. London, E. Murphy, and C. Steenbergen Regulation of the Ca2+ Gradient Across the Sarcoplasmic Reticulum in Perfused Rabbit Heart : A 19F Nuclear Magnetic Resonance Study Circ. Res., November 2, 1998; 83(9): 898 - 907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sato, D. G. Ferguson, H. Sako, G. W. Dorn II, V. J. Kadambi, A. Yatani, B. D. Hoit, R. A. Walsh, and E. G. Kranias Cardiac-specific Overexpression of Mouse Cardiac Calsequestrin Is Associated with Depressed Cardiovascular Function and Hypertrophy in Transgenic Mice J. Biol. Chem., October 23, 1998; 273(43): 28470 - 28477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Hajjar, U. Schmidt, T. Matsui, J. L. Guerrero, K.-H. Lee, J. K. Gwathmey, G. W. Dec, M. J. Semigran, and A. Rosenzweig Modulation of ventricular function through gene transfer in vivo PNAS, April 28, 1998; 95(9): 5251 - 5256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Luo, G. Chu, Y. Sato, Z. Zhou, V. J. Kadambi, and E. G. Kranias Transgenic Approaches to Define the Functional Role of Dual Site Phospholamban Phosphorylation J. Biol. Chem., February 20, 1998; 273(8): 4734 - 4739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Chu, G. W. Dorn II, W. Luo, J. M. Harrer, V. J. Kadambi, R. A. Walsh, and E. G. Kranias Monomeric Phospholamban Overexpression in Transgenic Mouse Hearts Circ. Res., October 19, 1997; 81(4): 485 - 492. [Abstract] [Full Text]
|
|
|
|
|
|
R. Kelly and M. Buckingham Manipulating Myosin Light Chain 2 Isoforms In Vivo : A Transgenic Approach to Understanding Contractile Protein Diversity Circ. Res., May 19, 1997; 80(5): 751 - 753. [Full Text]
|
|
|
|
|
|
Y. Sato, H. Kiriazis, A. Yatani, A. G. Schmidt, H. Hahn, D. G. Ferguson, H. Sako, S. Mitarai, R. Honda, L. Mesnard-Rouiller, et al. Rescue of Contractile Parameters and Myocyte Hypertrophy in Calsequestrin Overexpressing Myocardium by Phospholamban Ablation J. Biol. Chem., March 16, 2001; 276(12): 9392 - 9399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Haghighi, A. G. Schmidt, B. D. Hoit, A. G. Brittsan, A. Yatani, J. W. Lester, J. Zhai, Y. Kimura, G. W. Dorn II, D. H. MacLennan, et al. Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure J. Biol. Chem., June 22, 2001; 276(26): 24145 - 24152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jane Lalli, J. Yong, V. Prasad, K. Hashimoto, D. Plank, G. J. Babu, D. Kirkpatrick, R. A. Walsh, M. Sussman, A. Yatani, et al. Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) 1a Structurally Substitutes for SERCA2a in the Cardiac Sarcoplasmic Reticulum and Increases Cardiac Ca2+ Handling Capacity Circ. Res., July 20, 2001; 89(2): 160 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. DAVIA, R. J. HAJJAR, C. M. N. TERRACCIANO, N. S. KENT, H. K. RANU, P. O'GARA, A. ROSENZWEIG, and S. E. HARDING Functional alterations in adult rat myocytes after overexpression of phospholamban with use of adenovirus Physiol Genomics, August 31, 1999; 1(2): 41 - 50. [Abstract] [Full Text] [PDF]
|
|