(Circulation. 1995;92:778-784.)
© 1995 American Heart Association, Inc.
Articles |
Alterations of Sarcoplasmic Reticulum Proteins in Failing Human Dilated Cardiomyopathy
From the Medizinische Klinik II und III, Universität Freiburg, Germany (M.M., W.S., B.P., C. Holubarsch, C. Heilmann, H.J., G.H.); the Klinik für Thorax und Kardiovaskularchirurgie, Herzzentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (H.P.); the Shionogi Institute for Medical Science, Osaka, Japan (G.K.); and the Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Japan (K.M.).
Correspondence to Gerd Hasenfuss, MD, Medizinische Klinik III, Universität Freiburg, Hugstetter Str 55, 79106 Freiburg, Germany.
Background Previous studies provide considerable evidence that excitation-contraction coupling may be disturbed at the level of the sarcoplasmic reticulum (SR) in the failing human heart. Disturbed SR function may result from altered expression of calcium-handling proteins.
Methods and Results Levels of SR proteins involved in calcium release (ryanodine receptor), calcium binding (calsequestrin, calreticulin), and calcium uptake (calcium ATPase, phospholamban) were measured by Western blot analysis in nonfailing human myocardium (n=7) and in end-stage failing myocardium due to dilated cardiomyopathy (n=14). The levels of the ryanodine receptor, calsequestrin, and calreticulin were not significantly different in nonfailing and failing human myocardium. Phospholamban protein levels (pentameric form) normalized per total protein were decreased by 18% in the failing myocardium (P<.05). However, phospholamban protein levels were not significantly different in failing and nonfailing myocardium when normalization was performed per calsequestrin. Protein levels of SR calcium ATPase, normalized per total protein or per calsequestrin, were decreased by 41% (P<.001) or 33% (P<.05), respectively, in the failing myocardium. Furthermore, SR calcium ATPase was decreased relative to ryanodine receptor by 37% (P<.05) and relative to phospholamban by 28% (P<.05).
Conclusions Levels of SR proteins involved in calcium binding and release are unchanged in failing dilated cardiomyopathy. In contrast, protein levels of calcium ATPase involved in SR calcium uptake are reduced in the failing myocardium. Moreover, SR calcium ATPase is decreased relative to its inhibitory protein, phospholamban. These findings support the concept that reduced capacity of the SR to accumulate calcium may reflect a major defect in excitation-contraction coupling in human heart failure.
Key Words: sarcoplasmic reticulum • calcium • heart failure • ryanodine
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B. Pieske, L. S. Maier, D. M. Bers, and G. Hasenfuss Ca2+ Handling and Sarcoplasmic Reticulum Ca2+ Content in Isolated Failing and Nonfailing Human Myocardium Circ. Res., July 9, 1999; 85(1): 38 - 46. [Abstract] [Full Text] [PDF]
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A. Meissner, J.-Y. Min, N. Haake, S. Hirt, and R. Simon Dantrolene sodium improves the force-frequency relationship and {beta}-adrenergic responsiveness in failing human myocardium Eur J Heart Fail, June 1, 1999; 1(2): 177 - 186. [Abstract] [Full Text] [PDF]
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L. Hittinger, B. Ghaleh, J. Chen, J. G. Edwards, R. K. Kudej, M. Iwase, S.-J. Kim, S. F. Vatner, and D. E. Vatner Reduced Subendocardial Ryanodine Receptors and Consequent Effects on Cardiac Function in Conscious Dogs With Left Ventricular Hypertrophy Circ. Res., May 14, 1999; 84(9): 999 - 1006. [Abstract] [Full Text] [PDF]
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G. F. Tomaselli and E. Marban Electrophysiological remodeling in hypertrophy and heart failure Cardiovasc Res, May 1, 1999; 42(2): 270 - 283. [Full Text] [PDF]
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B. J.J.M. Brundel, I. C. Van Gelder, R. H. Henning, A. E. Tuinenburg, L. E. Deelman, R. G. Tieleman, J. G. Grandjean, W. H. Van Gilst, and H. J.G.M. Crijns Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation Cardiovasc Res, May 1, 1999; 42(2): 443 - 454. [Abstract] [Full Text] [PDF]
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B. Hoch, R. Meyer, R. Hetzer, E.-G. Krause, and P. Karczewski Identification and Expression of {delta}-Isoforms of the Multifunctional Ca2+/Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium Circ. Res., April 2, 1999; 84(6): 713 - 721. [Abstract] [Full Text] [PDF]
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U. Kirchhefer, W. Schmitz, H. Scholz, and J. Neumann Activity of cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human hearts Cardiovasc Res, April 1, 1999; 42(1): 254 - 261. [Abstract] [Full Text] [PDF]
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R. L. Winslow, J. Rice, S. Jafri, E. Marban, and B. O'Rourke Mechanisms of Altered Excitation-Contraction Coupling in Canine Tachycardia-Induced Heart Failure, II : Model Studies Circ. Res., March 19, 1999; 84(5): 571 - 586. [Abstract] [Full Text] [PDF]
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K. Dipla, J. A. Mattiello, K. B. Margulies, V. Jeevanandam, and S. R. Houser The Sarcoplasmic Reticulum and the Na+/Ca2+ Exchanger Both Contribute to the Ca2+ Transient of Failing Human Ventricular Myocytes Circ. Res., March 5, 1999; 84(4): 435 - 444. [Abstract] [Full Text] [PDF]
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S. R. Houser and E. G. Lakatta Function of the Cardiac Myocyte in the Conundrum of End-Stage, Dilated Human Heart Failure Circulation, February 9, 1999; 99(5): 600 - 604. [Full Text] [PDF]
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G. Hasenfuss, W. Schillinger, S. E. Lehnart, M. Preuss, B. Pieske, L. S. Maier, J. Prestle, K. Minami, and H. Just Relationship Between Na+-Ca2+–Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium Circulation, February 9, 1999; 99(5): 641 - 648. [Abstract] [Full Text] [PDF]
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S. Currie and G. L. Smith Enhanced phosphorylation of phospholamban and downregulation of sarco/endoplasmic reticulum Ca2+ ATPase type 2 (SERCA 2) in cardiac sarcoplasmic reticulum from rabbits with heart failure Cardiovasc Res, January 1, 1999; 41(1): 135 - 146. [Abstract] [Full Text] [PDF]
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F. G. Spinale, R. Mukherjee, R. S. Krombach, M. J. Clair, J. W. Hendrick, W. V. Houck, L. Hebbar, S. B. Kribbs, J. L. Zellner, and M. G. Dodd Chronic Amlodipine Treatment During the Development of Heart Failure Circulation, October 20, 1998; 98(16): 1666 - 1674. [Abstract] [Full Text] [PDF]
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H. K. B. SIMMERMAN and L. R. JONES Phospholamban: Protein Structure, Mechanism of Action, and Role in Cardiac Function Physiol Rev, October 1, 1998; 78(4): 921 - 947. [Abstract] [Full Text] [PDF]
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B. S. Cain, D. R. Meldrum, K. S. Joo, J.-F. Wang, X. Meng, J. C. Cleveland Jr., A. Banerjee, and A. H. Harken Human SERCA2a levels correlate inversely with age in senescent human myocardium J. Am. Coll. Cardiol., August 1, 1998; 32(2): 458 - 467. [Abstract] [Full Text] [PDF]
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K. Igarashi-Saito, H. Tsutsui, S. Yamamoto, M. Takahashi, S. Kinugawa, H. Tagawa, M. Usui, M. Yamamoto, K. Egashira, and A. Takeshita Role of SR Ca2+-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H31 - H40. [Abstract] [Full Text] [PDF]
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P. A Doevendans, M. J. Daemen, E. D de Muinck, and J. F Smits Cardiovascular phenotyping in mice Cardiovasc Res, July 1, 1998; 39(1): 34 - 49. [Abstract] [Full Text] [PDF]
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O. Zolk, M. Flesch, G. Nickenig, P. Schnabel, and M. Bohm Alteration of intracellular Ca2+-handling and receptor regulation in hypertensive cardiac hypertrophy: insights from Ren2-transgenic rats Cardiovasc Res, July 1, 1998; 39(1): 242 - 256. [Abstract] [Full Text] [PDF]
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L. Priebe and D. J. Beuckelmann Simulation Study of Cellular Electric Properties in Heart Failure Circ. Res., June 15, 1998; 82(11): 1206 - 1223. [Abstract] [Full Text] [PDF]
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H. Luss, P. Bokniek, G. Heusch, F. U. Muller, J. Neumann, W. Schmitz, and R. Schulz Expression of calcium regulatory proteins in short-term hibernation and stunning in the in situ porcine heart Cardiovasc Res, March 1, 1998; 37(3): 606 - 617. [Abstract] [Full Text] [PDF]
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G. Hasenfuss Alterations of calcium-regulatory proteins in heart failure Cardiovasc Res, February 1, 1998; 37(2): 279 - 289. [Full Text] [PDF]
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A. D Wickenden, R. Kaprielian, Z. Kassiri, J. N Tsoporis, R. Tsushima, G. I Fishman, and P. H Backx The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure Cardiovasc Res, February 1, 1998; 37(2): 312 - 323. [Abstract] [Full Text] [PDF]
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R. M Phillips, P. Narayan, A. M Gomez, K. Dilly, L. R Jones, W.J. Lederer, and R. A Altschuld Sarcoplasmic reticulum in heart failure: central player or bystander? Cardiovasc Res, February 1, 1998; 37(2): 346 - 351. [Full Text] [PDF]
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M. A Movsesian and R. H.G Schwinger Calcium sequestration by the sarcoplasmic reticulum in heart failure Cardiovasc Res, February 1, 1998; 37(2): 352 - 359. [Full Text] [PDF]
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M. Meyer and W. H Dillmann Sarcoplasmic reticulum Ca2+-ATPase overexpression by adenovirus mediated gene transfer and in transgenic mice Cardiovasc Res, February 1, 1998; 37(2): 360 - 366. [Abstract] [Full Text] [PDF]
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P. P de Tombe Altered contractile function in heart failure Cardiovasc Res, February 1, 1998; 37(2): 367 - 380. [Abstract] [Full Text] [PDF]
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M. C. Schaub, M. A. Hefti, R. A. Zuellig, and I. Morano Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms Cardiovasc Res, February 1, 1998; 37(2): 381 - 404. [Abstract] [Full Text] [PDF]
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K. R Sipido, T. Stankovicova, W. Flameng, J. Vanhaecke, and F. Verdonck Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure Cardiovasc Res, February 1, 1998; 37(2): 478 - 488. [Abstract] [Full Text] [PDF]
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G.A. Ng, S. M Cobbe, and G. L Smith Non-uniform prolongation of intracellular Ca2+ transients recorded from the epicardial surface of isolated hearts from rabbits with heart failure Cardiovasc Res, February 1, 1998; 37(2): 489 - 502. [Abstract] [Full Text] [PDF]
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C. F. McTiernan, B. H. Lemster, C. Frye, S. Brooks, A. Combes, and A. M. Feldman Interleukin-1ß Inhibits Phospholamban Gene Expression in Cultured Cardiomyocytes Circ. Res., October 19, 1997; 81(4): 493 - 503. [Abstract] [Full Text]
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F. G. Spinale, R. Mukherjee, J. P. Iannini, S. Whitebread, L. Hebbar, M. J. Clair, D. M. Melton, M. H. Cox, P. B. Thomas, and P. B. Marc de Gasparo Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure : II. Effects on Myocyte Contractile Processes Circulation, October 7, 1997; 96(7): 2397 - 2406. [Abstract] [Full Text]
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R. J. Hajjar, U. Schmidt, J. X. Kang, T. Matsui, and A. Rosenzweig Adenoviral Gene Transfer of Phospholamban in Isolated Rat Cardiomyocytes : Rescue Effects by Concomitant Gene Transfer of Sarcoplasmic Reticulum Ca2+-ATPase Circ. Res., August 19, 1997; 81(2): 145 - 153. [Abstract] [Full Text]
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F. J. Giordano, H. He, P. McDonough, M. Meyer, M. R. Sayen, and W. H. Dillmann Adenovirus-Mediated Gene Transfer Reconstitutes Depressed Sarcoplasmic Reticulum Ca2+-ATPase Levels and Shortens Prolonged Cardiac Myocyte Ca2+ Transients Circulation, July 15, 1997; 96(2): 400 - 403. [Abstract] [Full Text]
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