Superinhibition of sarcoplasmic reticulum function by phospholamban induces cardiac contractile failure

To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca2+ transport may drive the progressive functional deterioration lea ding to heart failure, transgenic mice, overexpressing a phospholamban Val( 49) --> Gly mutant (2-fold), which is a superinhibitor of SR Ca2+-ATPase af finity for Ca2+, were generated, and their cardiac phenotype was examined l ongitudinally. At 3 months of age, the increased EC50 level of SR Ca2+ upta ke for Ca2+ (0.67 +/- 0.09 mum) resulted in significantly higher depression of cardiomyocyte rates of shortening (57%), relengthening (31%), and prolo ngation of the Ca2+ signal decay time (165%) than overexpression (2-fold) o f wild type phospholamban (68%, 64%, and 125%, respectively), compared with controls (100%). Echocardiography also revealed significantly depressed fu nction and impaired beta -adrenergic responses in mutant hearts. The depres sed contractile parameters were associated with left ventricular remodeling , recapitulation of fetal gene expression, and hypertrophy, which progresse d to dilated cardiomyopathy with interstitial tissue fibrosis and death by 6 months in males. Females also had ventricular hypertrophy at 3 months but exhibited normal systolic function up to 12 months of age. These results s uggest a causal relationship between defective SR Ca2+ cycling and cardiac remodeling leading to heart failure, with a gender-dependent influence on t he time course of these alterations.