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(Circulation. 2004;110:3553-3559.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Excessive Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Expression Causes Increased Sarcoplasmic Reticulum Ca²⁺ Uptake but Decreases Myocyte Shortening

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

From the Department of Cardiology and Pneumology, University of Göttingen, Göttingen, Germany (N.T., J.P., T.S., P.S., S.W., H.K., G.H.); Biochemistry and Molecular Biology, University of Maryland, Baltimore (G.I.); the Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill (D.M.B.); and the Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK (S.C., E.B.E., D.F.R., G.L.S.).

Correspondence to Gerd Hasenfuss, MD, Department of Cardiology and Pneumology, University of Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany. E-mail hasenfus{at}med.uni-goettingen.de

Received June 20, 2003; de novo received December 22, 2003; revision received March 30, 2004; accepted April 4, 2004.

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 ß-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 K_m 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.

Key Words: heart failure • gene therapy • calcium • sarcoplasmic reticulum

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