Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation

Cardiac-specific overexpression of murine cardiac calsequestrin results in depressed cardiac contractile parameters, low Ca2+-induced Ca2+ release fro m sarcoplasmic reticulum (SR) and cardiac hypertrophy in transgenic mice. T o 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 i n calsequestrin overexpressing mice led to reversal of the depressed cardia c contractile parameters in Langendorff-perfused hearts or in vivo. This wa s associated with increases of SR Ca2+ storage, assessed by caffeine-induce d Na+-Ca2+ exchanger currents. The inactivation time of the L-type Ca2+ cur rent (I-Ca) which has an inverse correlation with Ca2+-induced SR Ca2+ rele ase, and the relation between the peak current density and half-inactivatio n time were also normalized, indicating a restoration in the ability of I-C a to trigger SR Ca2+ release. The prolonged action potentials in calsequest rin overexpressing cardiomyocytes also reversed to normal upon phospholamba n ablation. Furthermore, ablation of phospholamban restored the expression levels of atrial natriuretic factor and alpha -skeletal actin mRNA as well as ventricular myocyte size. These results indicate that attenuation of pho spholamban function may pr-event or overcome functional and remodeling defe cts in hypertrophied hearts.