ALTERATIONS OF SARCOPLASMIC-RETICULUM PROTEINS IN FAILING HUMAN DILATED CARDIOMYOPATHY

Background Previous studies provide considerable evidence that excitat ion-contraction coupling may be disturbed at the level of the sarcopla smic reticulum (SR) in the failing human heart. Disturbed SR function may result from altered expression of calcium-handling proteins. Metho ds and Results Levels of SR proteins involved in calcium release (ryan odine receptor), calcium binding (calsequestrin, calreticulin), and ca lcium uptake (calcium ATPase, phospholamban) were measured by Western blot analysis in nonfailing human myocardium (n=7) and in end-stage fa iling myocardium due to dilated cardiomyopathy (n=14). The levels of t he ryanodine receptor, calsequestrin, and calreticulin were not signif icantly different in nonfailing and failing human myocardium. Phosphol amban protein levels (pentameric form) normalized per total protein we re decreased by 18% in the failing myocardium (P<.05). However, phosph olamban protein levels were not significantly different in failing and nonfailing myocardium when normalization was performed per calsequest rin. 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 ATPas e was decreased relative to ryanodine receptor by 37% (P<.05) and rela tive to phospholamban by 28% (P<.05).Conclusions Levels of SR proteins involved in calcium binding and release are unchanged in failing dila ted cardiomyopathy. In contrast, protein levels of calcium ATPase invo lved in SR calcium uptake are reduced in the failing myocardium. Moreo ver, SR calcium ATPase is decreased relative to its inhibitory protein , phospholamban. These findings support the concept that reduced capac ity of the SR to accumulate calcium may reflect a major defect in exci tation-contraction coupling in human heart failure.