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

Dilated cardiomyopathy and end-stage heart failure result in multiple defec ts in cardiac excitation-contraction coupling. Via complementation of a gen etically based mouse model of dilated cardiomyopathy, we now provide eviden ce that progressive chamber dilation and heart failure are dependent on a C a2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, ph ospholamban, rescued the spectrum of phenotypes that resemble human heart f ailure. Inhibition of phospholamban-SERCA2a interaction via in vivo express ion of a phospholamban point mutant dominantly activated the contractility of ventricular muscle cells. Thus, interfering with phospholamban-SERCA2a i nteraction may provide a novel therapeutic approach for preventing the prog ression of dilated cardiomyopathy.