Overexpression of the Na+/Ca2+ exchanger and inhibition of the sarcoplasmic reticulum Ca2+-ATPase in ventricular myocytes from transgenic mice

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 V-max for the Ca2+ flux via SERCA and found to be 28%. In TR myocytes V-max 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. (C) 2001 Elsevier Science B.V. All rights reserved.