(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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