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Cardiovascular Research 2004 62(3):468-480; doi:10.1016/j.cardiores.2004.02.006
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model

Andrzej M Janczewskia, Maliha Zahida, Bonnie H Lemstera, Carol S Fryea, Gregory Gibsona, Yoshihiro Higuchib, Evangelia G Kraniasc, Arthur M Feldmanb and Charles F McTiernan*,a

aCardiovascular Institute, University of Pittsburgh, 200 Lothrop Street, 1744.1 BST, Pittsburgh, PA 15213, USA
bDepartment of Medicine, Thomas Jefferson University, USA
cDepartment of Pharmacology and Cell Biophysics, University of Cincinnati, USA

* Corresponding author. Tel.: +1-412-648-3016; fax: +1-412-383-8857. Email address: mctiernanc{at}msx.upmc.edu

Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Cai2+) transients may underlie the diminished cardiac function observed in heart failure. These alterations occur in humans and animals with heart failure, including the TNF1.6 mouse model, in which heart failure arises from cardiac-specific overexpression of tumor necrosis factor {alpha} (TNF{alpha}). Objective: Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca2+ pump, enhances SR Ca2+ uptake and increases contractility, we assessed whether ablation of phospholamban expression could improve cardiac function, limit remodeling, and improve survival in the TNF1.6 model of heart failure. Methods: We bred PLBKO with TNF1.6 mice and characterized the progeny for survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and Cai2+ transients and contractile function of isolated cardiomyocytes. Results: PLB ablation did not improve survival, cardiac function, or limit cardiac chamber dilation and hypertrophy in TNF1.6 mice (TKO mice). However, contractile function and Cai2+ transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Cai2+ cycling and cardiomyocyte contractile parameters may arise from a continued overexpression of collagen and decreased expression of gap junction proteins (connexin 43) in response to chronic TNF{alpha} stimulation. Conclusions: Enhancement of intrinsic cardiomyocyte Cai2+ cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.

KEYWORDS Calcium pump; Contractile function; Cytokines; Heart failure; Transgenic animal models; Mice

Abbreviations: PLB, phospholamban • SERCA, sarcoplasmic reticulum Ca2+ATPase • UTR, untranslated region • WT, wild type • KO, PLB knockout • Tg, TNF1.6 transgenic • TKO, TNF1.6 lacking PLB • FS%, percent fractional shortening • EDD, end diastolic dimension • ESD, end systolic dimension • GAPDH, glyceraldehyde phosphate dehydrogenase • NCX, sodium calcium exchanger

Time for primary review 26 days


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