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

Teucher, N. et al. (2004) Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening. Circulation, 110(23), pp. 3553-3559. (doi:10.1161/01.CIR.0000145161.48545.B3)

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Abstract

Background - 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. Methods and Results - Rabbit isolated cardiomyocytes were transfected at different multiplicities of infection (MOIs) with adenoviruses encoding SERCA1a (or beta-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 V-max 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Elliott, Dr Elspeth
Authors: Teucher, N., Prestle, J., Seidler, T., Currie, S., Elliott, E., Reynolds, D., Schott, P., Wagner, S., Kogler, H., Inesi, G., Bers, D., Hasenfuss, G., and Smith, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences
Journal Name:Circulation
ISSN:0009-7322

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