Cardiac-specific overexpression of murine cardiac calsequestrin results in depressed cardiac contractile parameters, low Ca 2؉ -induced Ca 2؉ release from sarcoplasmic reticulum (SR) and cardiac hypertrophy in transgenic mice. To test the hypothesis that inhibition of phospholamban activity may rescue some of these phenotypic alterations, the calsequestrin overexpressing mice were cross-bred with phospholamban-knockout mice. Phospholamban ablation in calsequestrin overexpressing mice led to reversal of the depressed cardiac contractile parameters in Langendorff-perfused hearts or in vivo. This was associated with increases of SR Ca 2؉ storage, assessed by caffeine-induced Na ؉ -Ca 2؉ exchanger currents. The inactivation time of the L-type Ca 2؉ current (I Ca ), which has an inverse correlation with Ca 2؉ -induced SR Ca 2؉ release, and the relation between the peak current density and half-inactivation time were also normalized, indicating a restoration in the ability of I Ca to trigger SR Ca 2؉ release. The prolonged action potentials in calsequestrin overexpressing cardiomyocytes also reversed to normal upon phospholamban ablation. Furthermore, ablation of phospholamban restored the expression levels of atrial natriuretic factor and ␣-skeletal actin mRNA as well as ventricular myocyte size. These results indicate that attenuation of phospholamban function may prevent or overcome functional and remodeling defects in hypertrophied hearts.Hypertrophy of ventricular myocardium is postulated to be an adaptive response to relative increases in external workload, induced by endocrine, paracrine, autocrine, and mechanical factors or decreased myocardial contractility (1). The increase in heart mass has been implicated to normalize cardiac function by decreasing wall stress. However, a sustained imbalance between workload and muscle contractility may lead to progressive thinning of the left ventricular wall and chamber dilation associated with decompensated hypertrophy and heart failure (2, 3). Studies in human and animal models have shown that cardiac hypertrophy is associated with impaired sarcoplasmic reticulum (SR) 1 Ca 2ϩ modulation, leading to aberrant cardiac contraction and relaxation (4 -8). Although several Ca 2ϩ -related signaling molecules, such as calcineurin, Ca 2ϩ -calmodulin kinase, and Ca 2ϩ

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