Background—Low activity of the sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA2a) resulting from strong inhibition by phospholamban (PLN) can depress cardiac contractility and lead to dilated cardiomyopathy and heart failure. Here, we investigated whether PLN exhibits cardiotoxic effects via mechanisms other than chronic inhibition of SERCA2a by studying a PLN mutant, PLN^R9C, that triggers cardiac failure in humans and mice.

Methods and Results—Because PLN^R9C inhibits SERCA2a mainly by preventing deactivation of wild-type PLN, SERCA2a activity could be increased stepwise by generating mice that carry a PLN^R9C transgene and 2, 1, or 0 endogenous PLN alleles (PLN^+/++TgPLN^R9C, PLN^+/-+TgPLN^R9C, and PLN^-/-+TgPLN^R9C, respectively). PLN^-/- +TgPLN^R9C hearts demonstrated accelerated sarcoplasmic reticulum Ca²⁺ uptake rates and improved hemodynamics compared with PLN^+/++TgPLN^R9C mice but still responded poorly to -adrenergic stimulation because PLN^R9C impairs protein kinase A–mediated phosphorylation of both wild-type and mutant PLN. PLN^+/++TgPLN^R9C mice died of heart failure at 21±6 weeks, whereas heterozygous PLN^+/-+TgPLN^R9C mice survived to 48±11 weeks, PLN^-/-+TgPLN^R9C mice to 66±19 weeks, and wild-type mice to 94±27 weeks (P<0.001). Although Ca²⁺ reuptake kinetics in young PLN^-/-+TgPLN^R9C mice exceeded those measured in wild-type control animals, this parameter alone was not sufficient to prevent the eventual development of dilated cardiomyopathy.

Conclusions—The data demonstrate an association between the dose-dependent inhibition of SERCA2a activity by PLN^wt and the time of onset of heart failure and show that a weak inhibitor of SERCA2a, PLN^R9C, which is diminished in its ability to modify the level of SERCA2a activity, leads to heart failure despite fast sarcoplasmic reticulum Ca²⁺ reuptake.