Excessive Sarcoplasmic/Endoplasmic Reticulum Ca 2+ -ATPase Expression Causes Increased Sarcoplasmic Reticulum Ca 2+ Uptake but Decreases Myocyte Shortening

Authors:
Publisher website
Google Scholar
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 Ca 2+ 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 P P 2+ 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 2+ transient amplitude was increased in Ad-SERCA1a–infected myocytes at MOI 10 (by 121%, P 2+ transient amplitude was not significantly changed. Caffeine-induced Ca 2+ transients indicated significantly increased SR Ca 2+ 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 Ca 2+ -ATPase uptake activity at MOI 50 (and increased cytosolic Ca 2+ buffering) is sufficient to curtail the Ca 2+ transient amplitude and explain the reduced contraction. Conclusions— Moderate SERCA1a gene transfer and expression improve contractility and Ca 2+ cycling. However, higher SERCA1a expression levels can impair myocyte shortening because of higher SERCA activity and Ca 2+ buffering.

This publication has 16 references indexed in Scilit: