Calcium pump overexpression and myocardial function. Implications for gene therapy of myocardial failure.

Abstract

The contraction-relaxation cycle of the heart is controlled by the sequential rise and fall of the cytosolic calcium concentration. Calcium entry through L-type calcium channels during the action potential serves to trigger calcium release from the sarcoplasmic reticulum (SR) leading to activation of contractile proteins and force generation (for review, see Reference 11 ). In addition, there is calcium influx by reverse-mode sodium-calcium exchange. The contribution of calcium influx through L-type calcium channels, or sodium calcium exchange, and of SR calcium release to systolic calcium transients differs from species to species.2 The global increase in calcium is immediately followed by calcium removal, resulting in subsequent deactivation of the contractile machinery and myocardial relaxation. Calcium removal from the cytosol occurs by the activity of the SR pump, by exchange of calcium for sodium via the sarcolemmal sodium-calcium exchanger (Na+-Ca2+ exchanger), by mitochondrial calcium uptake, and by calcium extrusion via the sarcolemmal calcium pump.1 Again, the contribution of these systems removing calcium from the cytosol to the decay of the calcium transient and to subsequent relaxation varies in a species-dependent manner. Using the rapid-cooling contracture technique, Bers et al suggested that in rat ventricular myocardium, ≈92% of calcium removal occurs by SR calcium uptake and only ≈7% by Na+-Ca2+ exchange.3 4 In other species (human, rabbit, ferret, cat, and guinea pig) the balance is more in the range of 70% to 75% SR calcium uptake and 25% to 30% Na+-Ca2+ exchange.3 4 According to these studies, calcium uptake by mitochondria and transsarcolemmal calcium extrusion by the sarcolemmal calcium pump were suggested to be of minor importance. The relevance of calcium extrusion by the sarcolemmal calcium pump is again evaluated in the study by Hammes et al5 in …