© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Overexpression of the Na+/Ca2+ exchanger and inhibition of the sarcoplasmic reticulum Ca2+-ATPase in ventricular myocytes from transgenic mice
aImperial College School of Medicine at NHLI, Cardiac Medicine, Dovehouse Street, London SW3 6LY, UK
bDepartments of Physiology and Medicine, UCLA, Los Angeles, CA, USA
* Corresponding author. Tel.: +44-171-352-8121; fax: +44-171-351-8145 c.terracciano{at}ic.ac.uk
Background: Myocytes from failing hearts produce slower and smaller Ca2+ transients associated with reduction in expression of sarcoplasmic reticulum (SR) Ca2+ ATPase and an overexpression of Na+/Ca2+ exchanger. Since the physiological role of both these proteins is competing for, and removing, Ca2+ from the cytoplasm, overexpression of the exchanger may compensate for less effective SR Ca2+ uptake. This study demonstrates this compensatory effect and provides a quantitative description of the results. Methods: Ventricular myocytes from transgenic mice overexpressing the Na+/Ca2+ exchanger (TR) and nontransgenic littermates (NON) were used. Cell shortening, cytoplasmic [Ca] (using indo-1 AM) and electrophysiological parameters were monitored. Results: TR myocytes displayed faster Ca2+ transients and twitches compared with NON myocytes. Superfusion with thapsigargin prolonged the time-course of Ca2+ transients of TR myocytes until these were equal to the ones measured in NON myocytes. The amount of SR Ca2+-ATPase (SERCA) inhibition needed to obtain such transients was calculated as a function of Vmax for the Ca2+ flux via SERCA and found to be 28%. In TR myocytes Vmax for the Ca2+ flux via Na+/Ca2+exchange was 240% of NON myocytes. When Ca2+ transients in TR myocytes were slowed by thapsigargin to similar values to the ones recorded in NON myocytes, SR Ca2+ content was also correspondingly reduced. Conclusions: The results suggest that in pathophysiological conditions where there is a reduction in SERCA function, overexpression of Na+/Ca2+ exchanger can compensate and allow normal Ca2+ homeostasis to be maintained. In mouse ventricular myocytes a 2.4-fold increase in Na+/Ca2+ exchange activity compensates for a reduction in SERCA function by 28% so maintaining the duration of the Ca2+ transient.
KEYWORDS Na/Ca-exchanger; SR (function); Myocytes; Calcium (cellular); e–c coupling
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