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 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.
Minamisawa
S
S
Department of Medicine, and Center for Molecular Genetics, University of California at San Diego, La Jolla 92093-0613C, USA.
Hoshijima
M
M
Chu
G
G
Ward
C A
CA
Frank
K
K
Gu
Y
Y
Martone
M E
ME
Wang
Y
Y
Ross
J
J
Kranias
E G
EG
Giles
W R
WR
Chien
K R
KR
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006439:Hemodynamics / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D016277:Ventricular Function, Left; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D000099211:Phospholamban