Abstract
BACKGROUND: Low activity of the sarco(endo)plasmic reticulum Ca(2+)-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
Ca(2+) uptake rates and improved hemodynamics compared with PLN(+/+)+TgPLN(R9C)
mice but still responded poorly to beta-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 Ca(2+)
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
Ca(2+) reuptake.
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