Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy

Cell. 1999 Oct 29;99(3):313-22. doi: 10.1016/s0092-8674(00)81662-1.

Abstract

Dilated cardiomyopathy and end-stage heart failure result in multiple defects in cardiac excitation-contraction coupling. Via complementation of a genetically based mouse model of dilated cardiomyopathy, we now provide evidence that progressive chamber dilation and heart failure are dependent on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. Inhibition of phospholamban-SERCA2a interaction via in vivo expression of a phospholamban point mutant dominantly activated the contractility of ventricular muscle cells. Thus, interfering with phospholamban-SERCA2a interaction may provide a novel therapeutic approach for preventing the progression of dilated cardiomyopathy.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium-Binding Proteins / deficiency
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism*
  • Calcium-Transporting ATPases / antagonists & inhibitors
  • Calcium-Transporting ATPases / metabolism*
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology*
  • Disease Models, Animal
  • Disease Progression
  • Heart / physiology
  • Heart / physiopathology*
  • Hemodynamics / genetics
  • Hemodynamics / physiology*
  • Homeostasis
  • Humans
  • Mice
  • Mice, Knockout
  • Myocardial Contraction
  • Myocardium / pathology
  • Sarcoplasmic Reticulum / enzymology*
  • Ventricular Function, Left

Substances

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