Abstract P240: Mitochondrial Reactive Oxygen Species Regulate the Cardiac Na+ Channel in Heart Failure
Background: Previously, we have shown that elevated intracellular NADH causes a decrease in cardiac Na+ current (INa) signaled by an increase in mitochondrial reactive oxygen species (ROS). The decrease in INa can be ameliorated by NAD+ or a mitochondrial specific anti-oxidant, mitoTEMPO. It is known that cardiomyopathy is associated with reduced INa. Therefore, we tested whether the NADH-mitochondrial ROS pathway was involved in the reduction in INa in cardiomyopathic mice.
Methods: Nonischemic cardiomyopathy was induced in C57BL/6 mice 6 weeks after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt water substitution. Sham operated mice were used as controls. Ventricular myocytes isolated from mice were utilized for whole-cell patch clamp recording, intracellular NADH/NAD+ level measurements, and mitochondrial ROS monitoring with confocal microscopy.
Results: Compared to the sham mice, the left ventricular volume was significantly enlarged (105.5 ± 4.4 µL vs. 91.6 ± 4.0 µL, P<0.05), and the ejection fraction was significantly reduced (39.2 ± 1.6% vs. 48.7 ± 1.6%, P<0.05) in DOCA mice. Intracellular NADH level was increased (2.78-fold; P<0.01), and INa was decreased (62±8%; P<0.01) in myocytes of DOCA mice vs. sham. NAD+ (500 μ M) and mitoTEMPO (10 μ M) recovered INa (90±9% and 103±9% of sham, respectively, P>0.05). Mitochondrial ROS overproduction was observed with DOCA mice myocytes by MitoSOX Red (∼4.8-fold of sham; P<0.01). NAD+ and mitoTEMPO decreased ROS in DOCA mice myocytes (∼20±6% of DOCA for both, P<0.01).
Conclusions: NADH and mitochondrial ROS were elevated, and INa was decreased in nonischemic cardiomyopathy. Maneuvers that reduced mitochondrial ROS restored INa. Since reduced INa and the subsequent slow conduction velocity are thought to contribute to arrhythmic risk in this condition, NAD+ and mitochondrial anti-oxidants may have anti-arrhythmic activity in cardiomyopathy.
- © 2011 by American Heart Association, Inc.