Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening

Nils Teucher, Juergen Prestle, Tim Seidler, Susan Currie, Elspeth B. Elliott, Deborah F. Reynolds, Peter Schott, Stefan Wagner, Harald Kogler, Giuseppe Inesi, Donald M Bers, Gerd Hasenfuss, Godfrey L. Smith

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Background - Increasing sarcoplasmic/endoplasmic reticulum (SR) Ca 2+-ATPase (SERCA) uptake activity is a promising therapeutic approach for heart failure. We investigated the effects of different levels of SERCA1a expression on contractility and Ca2+ cycling. We tested whether increased SERCA1a expression levels enhance myocyte contractility in a gene-dose-dependent manner. Methods and Results - Rabbit isolated cardiomyocytes were transfected at different multiplicities of infection (MOIs) with adenoviruses encoding SERCA1a (or β-galactosidase as control). Myocyte relaxation half-time was decreased by 10% (P=0.052) at SERCA1a MOI 10 and by 28% at MOI 50 (P<0.05). Myocyte fractional shortening was increased by 12% at MOI 10 (P<0.05) but surprisingly decreased at MOI 50 (-22%, P<0.05) versus control. SR Ca2+ uptake (in permeabilized myocytes) demonstrated a gene-dose-dependent decrease in Km by 29% and 46% and an increase in Vmax by 37% and 72% at MOI 10 and MOI 50, respectively (all P<0.05 versus control). Ca2+ transient amplitude was increased in Ad-SERCA1a-infected myocytes at MOI 10 (by 121%, P<0.05), but at MOI 50, the Ca2+ transient amplitude was not significantly changed. Caffeine-induced Ca2+ transients indicated significantly increased SR Ca2+ content in Ad-SERCA1a-infected cells, by 72% at MOI 10 and by 87% at MOI 50. Mathematical simulations demonstrate that the functional increase in SR Ca2+-ATPase uptake activity at MOI 50 (and increased cytosolic Ca2+ buffering) is sufficient to curtail the Ca2+ transient amplitude and explain the reduced contraction. Conclusions - Moderate SERCA1a gene transfer and expression improve contractility and Ca2+ cycling. However, higher SERCA1a expression levels can impair myocyte shortening because of higher SERCA activity and Ca2+ buffering.

Original languageEnglish (US)
Pages (from-to)3553-3559
Number of pages7
JournalCirculation
Volume110
Issue number23
DOIs
StatePublished - Dec 7 2004
Externally publishedYes

Keywords

  • Calcium
  • Gene therapy
  • Heart failure
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Teucher, N., Prestle, J., Seidler, T., Currie, S., Elliott, E. B., Reynolds, D. F., Schott, P., Wagner, S., Kogler, H., Inesi, G., Bers, D. M., Hasenfuss, G., & Smith, G. L. (2004). Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening. Circulation, 110(23), 3553-3559. https://doi.org/10.1161/01.CIR.0000145161.48545.B3