Abstract 13435: Mitochondrial L-arginine Transport Capacity: Implications for Oxidative Stress and the Pathogenesis of Heart Failure
Accumulating evidence indicates that nitric oxide (NO) is a key regulator of cardiac mitochondrial metabolism and that an isoform of NO synthase exists within mitochondria. To date the biochemical basis for L-arginine (L-arg) transport has been unclear and whether alterations in mitochondrial L-arg transport influences mitochondrial metabolism and oxidative stress (ROS) is unknown. Moreover whether mitochondrial L-arg transport is altered in CVD is unknown. Accordingly in this study we aimed to characterize cardiac mitochondrial L-arg transport in the normal and failing heart, and determine whether its manipulation alters mitochondrial function or ROS. Isolated cardiac sheep mitochondria exhibited concentration dependent accumulation of [3H]-L-arg with biochemical features consistent with the y+ system. This was supported by detection of the CAT1 L-arg transporter by western blot and confocal microscopy. In mitochondria obtained from failing sheep hearts (rapid ventricular pacing for 4wks) we demonstrated a significant reduction in both L-arg uptake (p<0.001) and CAT1 expression (p<0.05). This was accompanied by significantly higher 3-nitrotyrosine levels (171 ± 0.3%, p<0.05) which may contribute to the altered mitochondrial function observed in heart failure. To test the hypothesis that mitochondrial L-arg availability influences the cellular response to stress, we examined the effect of mitochondrial specific overexpression of CAT1 (pCAT1-MTS) on CHO cells exposed to mitochondrial stress (hypoxia-reoxygenation and antimycin A treatment) as shown in the table below:
Taken together, these data provide new insights into the nature of mitochondrial L-arg transport, its role in mitochondrial biology and the pathogenesis of heart failure. Augmentation of mitochondrial L-arg may have therapeutic potential in CVD associated with abnormal mitochondrial function and elevated oxidative stress such as heart failure.
- © 2010 by American Heart Association, Inc.