Abstract 3862: Controlled Overexpression of Na+/Ca2+ Exchanger Does Not Lead to Heart Failure
In many, but not all models of heart failure (HF), Na+/Ca2+ exchanger (NCX1) expression is increased and hypothesized to contribute to contractile dysfunction. It is not clear whether NCX1 overexpression, by itself, can lead to HF. To simulate switching on NCX1 expression with onset of disease process, we have produced mice in which expression of the rat NCX1 transgene was induced when doxycycline was removed from the feed at 5 weeks. At 8 to 10 weeks, NCX1 expression in induced (Ind) mouse hearts was 2-fold higher but protein levels of sarco(endo)plasmic reticulum Ca2+-ATPase, α1- and α2-subunits of Na+-K+-ATPase, phospholamban, ryanodine receptor, calsequestrin, unphosphorylated and phosphorylated phospholemman were unchanged when compared to wild-type (WT) or non-induced (Non-Ind) hearts. There was no cellular hypertrophy since WT, Non-Ind and Ind myocytes had similar whole cell membrane capacitance. In Ind myocytes, NCX1 current amplitude was ~42% higher, L-type Ca2+ current amplitude was unchanged, and action potential duration was prolonged when compared to WT or Non-Ind myocytes. Contraction and [Ca2+]i transient amplitudes in Ind myocytes were lower at 0.6, not different at 1.8, and higher at 5.0 mM [Ca2+ current amplitude ]o when compared to WT or Non-Ind myocytes. Despite similar Ca2+ and SR Ca2+ uptake, SR Ca2+ content at 5.0 mM [Ca2+]o was significantly higher in Ind compared to Non-Ind myocytes, indicating that NCX1 directly contributed to SR Ca2+ loading. Echocardiography demonstrated that heart rate, left ventricular mass, ejection fraction, stroke volume and cardiac output were similar among the 3 groups of animals. In vivo close-chest catheterization demonstrated similar contractility (+dP/dt) and relaxation (−dP/dt) among the 3 groups of mice, both at baseline and after stimulation with isoproterenol. We conclude that induced NCX1 overexpression at levels found in diseased hearts, without concomitant changes in other proteins involved in excitation-contraction coupling, did not result in HF.