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.