Chronic Phospholamban–Sarcoplasmic Reticulum Calcium ATPase Interaction Is the Critical Calcium Cycling Defect in Dilated Cardiomyopathy

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 C...

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Bibliographic Details
Published in:Cell 1999-10, Vol.99 (3), p.313-322
Main Authors: Minamisawa, Susumu, Hoshijima, Masahiko, Chu, Guoxiang, Ward, Christopher A, Frank, Konrad, Gu, Yusu, Martone, Maryann E, Wang, Yibin, Ross, John, Kranias, Evangelia G, Giles, Wayne R, Chien, Kenneth R
Format: Article
Language:English
Subjects:
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
phospholamban
Sarcoplasmic Reticulum - enzymology
Ventricular Function, Left
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Summary: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 Ca 2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca 2+ 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.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(00)81662-1