Alterations of phospholamban function can exhibit cardiotoxic effects independent of excessive sarcoplasmic reticulum Ca2+-ATPase inhibition

Joachim P Schmitt, Ferhaan Ahmad, Kristina Lorenz, Lutz Hein, Stefan Schulz, Michio Asahi, David H Maclennan, Christine E Seidman, J G Seidman, Martin J Lohse
Circulation 2009 January 27, 119 (3): 436-44

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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"