Abstract 13496: Mitochondria are a Mediator of Altered Ca2+ Handling in Response to Cardiac NaI+ Overload.
Introduction. Altered intracellular calcium (Cai2+) handling is the main cause of arrhythmias induced by intracellular sodium (Nai+) overload. We hypothesized that cellular Na+ overload leads to increased mitochondrial Na+-Ca2+ exchange (mNCE) and reactive oxygen species (ROS) formation, and that reduction of mitochondrial NCE may reduce ROS formation and dysfunctional Ca2+ handling.
Methods. We used confocal fluorescent imaging of intact and membrane-permeabilized single rabbit and rat ventricular cardiac myocytes to study Cai2+ transients, Na+i and intracellular reactive oxygen species (ROS) levels. Cellular Na+ overload was induced using the late Na+ current (INaL) enhancer anemone toxin-II (ATX-II), and mNCE was inhibited by use of CGP.
Results. ATX-II (5 nM) increased the intracellular Nai+ concentration and caused abnormal Cai2+ transients in intact rabbit and rat myocytes. In addition, ATX-II significantly increased intracellular ROS levels. These effects were abolished by the INaL inhibitor ranolazine (10 μ M) or by pharmacological CaMKII inhibition with KN93 (10 μ M). The mNCE antagonist CGP (1 μ M) restored normal Ca2+ transients and ROS levels but had no effect on the intracellular Nai+ concentration. To confirm the effect of an increase of intracellular Nai+ on ROS and Cai2+ transients, we studied spontaneous Ca2+ waves in membrane permeabilized myocytes. Cell superfusion with 15 mM Na+ (cytosolic Ca2+ was fixed at 100 nM) resulted in an increase of ROS in mitochondria and Ca2+ leak from ryanodine receptors. The CaMKII inhibitor KN-93 (10 μ M) attenuated the effects of 15 mM Na+ on ROS and Ca2+ signaling.
Conclusions: These data suggest that mitochondria are a mediator of altered Ca2+ handling in response to cardiac Nai+ overload. An increase in Nai+ causes mitochondrial NCE and ROS production, which activates CaMKII and leads to altered Ca2+ transients and dysfunctional diastolic Ca2+ handling.
- Excitation-contraction coupling (ECC)
- Mitochondrial energetics, heart failure, arrhythmias
- Cell physiology
- © 2011 by American Heart Association, Inc.