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

Teucher, N. and Prestle, J. and Seidler, T. and Currie, S. and Elliott, E.B. and Reynolds, D.F. and Schott, P. and Wagner, S. and Kogler, H. and Inesi, G. and Bers, D.M. and Hasenfuss, G. and Smith, G.L. (2004) Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening. Circulation, 110. pp. 3553-3559. ISSN 0009-7322 (https://doi.org/10.1161/01.CIR.0000145161.48545.B3)

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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.

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