SARCOPLASMIC-RETICULUM CA(2-RNA AND PROTEIN-LEVELS IN END-STAGE HEART-FAILURE DUE TO ISCHEMIC OR DILATED CARDIOMYOPATHY()ATPASE AND PHOSPHOLAMBAN MESSENGER)

Abnormalities in intracellular Ca2+ handling play a crucial role in th e pathogenesis of heart failure. The reduced capacity of failing human myocardium to restore low resting Ca2+ levels during diastole has bee n explained by the impairment of Ca2+ uptake into the sarcoplasmic ret iculum (SR) via the SR Ca(2+)ATPase. It is unclear whether Ca(2+)ATPas e function, protein levels, and mRNA steady-state levels correspond to one other, and whether the cause of heart failure, namely idiopathic dilated or ischemic cardiomyopathy, produces different changes. The pr esent study examined SR Ca(2+)ATPase activity and both mRNA and protei n levels of SR Ca(2+)ATPase, phospholamban, and Gi alpha(2) in left ve ntricular myocardium from eight nonfailing hearts, from eight hearts o f patients with idiopathic dilated cardiomyopathy (DCM), and from six hearts from patients with ischemic cardiomyopathy (ICM). Compared to n onfailing myocardium, the activity of the SR Ca(2+)ATPase was signific antly reduced in failing myocardium from patients with DCM (36%, P<0.0 1) and from patients with ICM (37%, P<0.001). Significantly lower leve ls of SR Ca(2+)ATPase mRNA levels (55% and -56%, P<0.001 for DCM and I CM, respectively) and phospholamban mRNA (45%, P<0.001 for DCM; 31%, P <0.05 for ICM) were observed in failing than in nonfailing myocardium. In contrast, no significant changes were observed at the level of pro teins. Gi alpha(2) mRNA and protein levels were both significantly inc reased in failing mycocardium. There were no differences between idiop athic dilated and ischemic cardiomyopathy concerning the examined para meter. It is concluded that reduced SR Ca(2+)ATPase activity contribut es to an altered intracellular Ca2+ handling by the SR in both dilated and ischemic cardiomyopathic hearts. However, changes in SR Ca(2+)ATP ase and phospholamban steady-state protein levels do not contribute to these alterations. The dissociation between protein and mRNA levels p rovides evidence for a posttranscriptional or posttranslational regula tion of these proteins. The observed alterations are not dependent on the underlying cause of end-stage heart failure.