Rescue of the depressed contractile parameters in calsequestrin overexpressing hearts by phospholamban ablation

Abstract

Transgenic mice with cardiac-specific overexpression (20 fold) of calsequestrin exhibited: a) depressed contractile parameters in Langendorff preparations and isolated myocytes; b) prolongation in the inactivation time of the L-type Ca 2+ current 2(Ic~), which has an inverse correlation with Ca2+-induced SR Ca + release; and c) development of cardiac hypertrophy (30 % in heart/body weight), compared to wild-type littermates (WT). To determine whether this impaired excitation-contraction (E-C) coupling can be rescued by increases in the SR CaR*-ATPase activity through ablation of phospholamban, we crossbred phospholamban deficient mice (PLBKO) with the calsequestrin overexpression mice (CSQ+WT) and generated transgenic mice overexpressing calsequestrin (20 fold) in the phospholamban deficient hearts (CSQ+PLBKO). Transgenic hearts from CSQ+PLBKO exhibited significantly enhanced contractile parameters (_+dP/dt) in Langendorff preparations, shorter inactivation times (T~a) of Ic~, and lower increases in heart/body weight (8%), compared to those of CSQ+WT (Table). These results suggest that increases in the affinity of SR Ca2÷-ATPase for Ca 2+ restore the depressed contractile parameters, associated with calsequestrin overexpression. Thus, decreases in the expression levels or activity of phospholamban may overcome defects in E-C coupling and the development of hypertrophy in the heart.