Molecular mechanisms of reduced sarcoplasmic reticulum Ca(2+) uptake in human failing left ventricular myocardium

J Heart Lung Transplant. 2002 Mar;21(3):366-73. doi: 10.1016/s1053-2498(01)00390-4.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Calcium / metabolism*
  • Calcium-Binding Proteins / metabolism
  • Calcium-Transporting ATPases / metabolism
  • Cardiomyopathy, Dilated / metabolism
  • Child
  • Female
  • Heart Ventricles / metabolism
  • Humans
  • Male
  • Middle Aged
  • Myocardium / metabolism*
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Sarcoplasmic Reticulum / enzymology
  • Sarcoplasmic Reticulum / metabolism*


  • Calcium-Binding Proteins
  • phospholamban
  • Phosphoprotein Phosphatases
  • Calcium-Transporting ATPases
  • Calcium