Abstract 13826: ARC Inhibits Cardiac Hypertrophy Through Co-localisation With Mitochondrial NADH Dehydrogenase
Introduction: Mitochondria play important roles in myocardial hypertrophy, but the molecular link between mitochondrial dysfunction and cardiac hypertrophy remains unclear. In the present research we explored the roles of apoptosis repressor with caspase recruitment domain (ARC) in the development of cardiac hypertrophy and its underlying mitochondrial mechanisms.
Methods and Results: A wistar rat model of cardiac hypertrophy was established using abdominal aortic constriction (AAC). It is found that ARC was transported out of mitochondria during development of cardiomyocyte hypertrophy in vitro and in vivo, which was mediated by CK2 phosphorylation. The decrease of ARC content in mitochondria was accompanied by a decline in mitochondrial function and an increase level of reactive oxygen species (ROS). Furthermore, ARC was confirmed to co-localise with mitochondrial NADH dehydrogenase by analysis of blue-native gel electrophoresis and immunoprecipitation. ARC overexpression resulted in the increase of ARC level in mitochondria and in turn protected mitochondrial function by preserving mitochondrial NADH dehydrogenase activity. It was also found that ARC transport from mitochondria induced the damage of mitochondrial respiratory function and increase in ROS level, which promoted nuclear import of hypertrophic transcription factor (NFAT) and thus induced cardiomyocyte hypertrophy .
Conclusions: ARC was firstly found to be co-localised with mitochondrial NADH dehydrogenase in cardiomyocyte. During development of myocardial hypertrophy, ARC was transported out of mitochondria owing to a decrease in CK2 activity, which led to decreases in mitochondrial NADH dehydrogenase activity and increases in ROS level, and finally induced hypertrophy by promoting the nuclear import of NFAT.
Author Disclosures: Z. Mei: None. X. Wang: None. J. Gong: None. W. Liu: None. X. Gao: None. T. Zhang: None. L. Qian: None.
- © 2014 by American Heart Association, Inc.