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

N. Teucher, J. Prestle, T. Seidler, S. Currie, E.B. Elliott, D.F. Reynolds, P. Schott, S. Wagner, H. Kogler, G. Inesi, D.M. Bers, G. Hasenfuss, G.L. Smith

Research output: Contribution to journalArticle

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Abstract

Increasing sarcoplasmic/endoplasmic reticulum (SR) Ca2+-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. 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. 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.
LanguageEnglish
Pages3553-3559
Number of pages7
JournalCirculation
Volume110
DOIs
Publication statusPublished - 2004

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

Keywords

  • sarcoplasmic reticulum
  • myocyte shortening
  • reticulum Ca2+
  • circulation

Cite this

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

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

In: Circulation, Vol. 110, 2004, p. 3553-3559.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening

AU - Teucher, N.

AU - Prestle, J.

AU - Seidler, T.

AU - Currie, S.

AU - Elliott, E.B.

AU - Reynolds, D.F.

AU - Schott, P.

AU - Wagner, S.

AU - Kogler, H.

AU - Inesi, G.

AU - Bers, D.M.

AU - Hasenfuss, G.

AU - Smith, G.L.

PY - 2004

Y1 - 2004

N2 - Increasing sarcoplasmic/endoplasmic reticulum (SR) Ca2+-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. 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. 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 - Increasing sarcoplasmic/endoplasmic reticulum (SR) Ca2+-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. 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. 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 - sarcoplasmic reticulum

KW - myocyte shortening

KW - reticulum Ca2+

KW - circulation

U2 - 10.1161/01.CIR.0000145161.48545.B3

DO - 10.1161/01.CIR.0000145161.48545.B3

M3 - Article

VL - 110

SP - 3553

EP - 3559

JO - Circulation

T2 - Circulation

JF - Circulation

SN - 0009-7322

ER -