title: Molecular mechanisms of reduced sarcoplasmic reticulum Ca(2+) uptake in human failing left ventricular myocardium.
abstract: BACKGROUND
  Human failing heart due to idiopathic dilated cardiomyopathy is associated with decreased sarcoplasmic reticulum Ca(2+) uptake. However, it is unknown as to which mechanism leads to this abnormality.
  
  
  METHODS
  Immunodetectable sarcoplasmic reticulum proteins (phospholamban [PLB], phosphorylated PLB at serine-16 or threonine-17, calsequestrin and Ca(2+)-ATPase levels), the activities of Ca(2+)-calmodulin-dependent protein kinase and protein phosphatase and Ca(2+) uptake at varying Ca(2+) concentrations were determined in left ventricular specimens from the same 7 failing hearts (ejection fraction 20 +/- 2%) due to idiopathic dilated cardiomyopathy and 5 non-failing explanted control donor hearts.
  
  
  RESULTS
  In failing hearts, compared with control donors, decreased maximal velocity and affinity of Ca(2+) uptake for Ca(2+) were found to be associated with reduced expression levels of Ca(2+)-adenosine triphosphatase (ATPase), PLB and phosphorylated PLB at serine-16, but not of calsequestrin and phosphorylated PLB at threonine-17. In contrast, protein phosphatase activity increased significantly and the activity and protein expression level of the delta isoform of Ca(2+)-calmodulin-dependent protein kinase remained unchanged in failing hearts compared with control donors.
  
  
  CONCLUSIONS
  The impaired maximal velocity of sarcoplasmic reticulum Ca(2+) uptake may be due in part to reduced protein expression level of Ca(2+)-ATPase, whereas the reduced affinity may be due in part to the reduced ratio of Ca(2+)-ATPase to PLB and reduced PLB phosphorylation at serine-16 in failing hearts. The latter abnormality may be due in part to increased protein phosphatase activity. These results suggest that selective enhancement of Ca(2+) uptake into the sarcoplasmic reticulum by pharmaceutical agents, or by molecular tools that inhibit phosphatase activity, would be a valuable therapeutic approach for treating, or at least retarding, the process of heart failure.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA
authors.forename: Sudhish
authors.initials: S
authors.lastname: Mishra
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.forename: Nivedita
authors.initials: N
authors.lastname: Tiwari
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sharov
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D002648:Child; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D010749:Phosphoprotein Phosphatases; D000099211:Phospholamban