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Phospholamban Ablation Rescues SR Ca2+ Loading But Not Cardiac Function In CaMKIIλC Transgenic Mice
Author(s) -
Mishra Shikha,
Zhang Tong,
Guo Tao,
Bers Donald,
Brown Joan Heller
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1124
Subject(s) - phospholamban , genetically modified mouse , transgene , ablation , cardiology , medicine , chemistry , function (biology) , microbiology and biotechnology , biophysics , endocrinology , heart failure , biology , biochemistry , gene
Ca 2+ /calmodulin dependent kinase II (CaMKII) is a key candidate for controlling phosphorylation and function of Ca 2+ regulatory proteins of the sarcoplasmic reticulum (SR), including the ryanodine receptors (RyR2) and phospholamban (PLB). The predominant form of CaMKII in the heart is the λ isoform. Previous work from our laboratory has shown that transgenic (TG) mice overexpressing CaMKIIλ C in the heart develop dilated cardiomyopathy due to increased phosphorylation of the RyR2 and enhanced SR Ca 2+ leak. The associated lowering of SR Ca 2+ load likely contributes to decreased ventricular contractility. Since PLB limits SR Ca 2+ uptake, we hypothesized that PLB ablation would recover SR Ca 2+ load and rescue the heart failure phenotype. Accordingly, we crossed PLB −/ − mice with CaMKIIλ TG and found surprisingly, that the phenotype was exaggerated in the double mutant (DM) mice. DM showed severe dilated cardiomyopathy and contractile failure despite Ca 2+ load repletion, and normalized twitch Ca 2+ transients relative to TG. There was no significant change in expression levels of calsequestrin, SERCA, and Na + /Ca 2+ exchanger, major Ca 2+ handling proteins. RyR2 phosphorylation at known CaMKII sites (Ser2815 and 2809) was not greater in DM vs TG mice. However, SR Ca 2+ sparks were increased, presumably due to the normalized Ca 2+ load. Elevated Ca 2+ and CaMKII have been implicated in cardiomyocyte apoptosis and preliminary studies suggest an increase in TUNEL positive cells in DM. We are currently testing the hypothesis that increased apoptosis contributes to the more severe phenotype in DM vs TG.