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

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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

Fingerprint

Calcium-Transporting ATPases
Sarcoplasmic Reticulum
Endoplasmic Reticulum
Muscle Cells
Infection
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Galactosidases
Adenoviridae Infections
Caffeine
Cardiac Myocytes
Genes
Heart Failure
Rabbits
Gene Expression

Keywords

  • Calcium
  • Gene therapy
  • Heart failure
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening. / Teucher, Nils; Prestle, Juergen; Seidler, Tim; Currie, Susan; Elliott, Elspeth B.; Reynolds, Deborah F.; Schott, Peter; Wagner, Stefan; Kogler, Harald; Inesi, Giuseppe; Bers, Donald M; Hasenfuss, Gerd; Smith, Godfrey L.

In: Circulation, Vol. 110, No. 23, 07.12.2004, p. 3553-3559.

Research output: Contribution to journalArticle

Teucher, N, Prestle, J, Seidler, T, Currie, S, Elliott, EB, Reynolds, DF, Schott, P, Wagner, S, Kogler, H, Inesi, G, Bers, DM, Hasenfuss, G & Smith, GL 2004, 'Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening', Circulation, vol. 110, no. 23, pp. 3553-3559. https://doi.org/10.1161/01.CIR.0000145161.48545.B3
Teucher, Nils ; Prestle, Juergen ; Seidler, Tim ; Currie, Susan ; Elliott, Elspeth B. ; Reynolds, Deborah F. ; Schott, Peter ; Wagner, Stefan ; Kogler, Harald ; Inesi, Giuseppe ; Bers, Donald M ; Hasenfuss, Gerd ; Smith, Godfrey L. / Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening. In: Circulation. 2004 ; Vol. 110, No. 23. pp. 3553-3559.
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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.",
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AU - Prestle, Juergen

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AU - Currie, Susan

AU - Elliott, Elspeth B.

AU - Reynolds, Deborah F.

AU - Schott, Peter

AU - Wagner, Stefan

AU - Kogler, Harald

AU - Inesi, Giuseppe

AU - Bers, Donald M

AU - Hasenfuss, Gerd

AU - Smith, Godfrey L.

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N2 - 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.

AB - 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.

KW - Calcium

KW - Gene therapy

KW - Heart failure

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