Alterations of Phospholamban Function Can Exhibit Cardiotoxic Effects Independent of Excessive Sarcoplasmic Reticulum Ca -ATPase Inhibition

studying a PLN mutant, PLN, that triggers cardiac failure in humans and mice. Methods and Results—Because PLN inhibits SERCA2a mainly by preventing deactivation of wild-type PLN, SERCA2a activity could be increased stepwise by generating mice that carry a PLN transgene and 2, 1, or 0 endogenous PLN alleles (PLN / TgPLN, PLN / TgPLN, and PLN / TgPLN, respectively). PLN / TgPLN hearts demonstrated accelerated sarcoplasmic reticulum Ca uptake rates and improved hemodynamics compared with PLN / TgPLN mice but still responded poorly to -adrenergic stimulation because PLN impairs protein kinase A–mediated phosphorylation of both wild-type and mutant PLN. PLN / TgPLN mice died of heart failure at 21 6 weeks, whereas heterozygous PLN / TgPLN mice survived to 48 11 weeks, PLN / TgPLN mice to 66 19 weeks, and wild-type mice to 94 27 weeks (P 0.001). Although Ca reuptake kinetics in young PLN / TgPLN mice exceeded those measured in wild-type control animals, this parameter alone was not sufficient