Abstract 14114: p53-mediated Acceleration of Mitochondrial Oxygen Consumption Promotes Lipotoxicity via SCO2 in Diabetic Mice
Background: Altered myocardial metabolism is an important contributor in the development of diabetic cardiomyopathy. We have demonstrated that mitochondrial respiration is regulated by p53 via SCO2 (Synthesis of cytochrome c oxidase 2).
Methods and Results: We examined the role of p53 in the development of diabetic cardiomyopathy in both type I (streptozotocin (STZ) administration), and type II diabetes (db/db mice). In both models, cardiac contraction was declined (68% and 62% vs control) with remarkable induction of p53 protein in the heart (155% in db/db mice, 168% in STZ induced diabetic mice (STZ-WT) vs control). On the other hand, no cardiac dysfunction was observed in STZ induced diabetes model of p53KO (STZ-p53KO). Although there was no difference in the number of apoptotic myocytes, CD31 positive cells or fibrosis in both mice, we found that oxygen consumption of isolated heart mitochondria was increased and complex IV activity was up-regulated dramatically in STZ-WT(135% and 133% vs control). Accumulation of lipid droplets and 8-OHdG-stained myocytes were significantly increased in STZ-WT. Membrane-localized fatty acid translocase FAT/CD36 was more abundantly expressed in myocyte of STZ-WT mice (187% vs control). In cultured myocytes, induction of p53 or SCO2 significantly augmented the uptake of oleate and palmitate associated with accumulation of fatty acids (FA) in myocytes. Generation of reactive oxygen species (ROS) detected by DHE staining were also augmented. Furthermore, we induced diabetes with SCO2+/− mice by STZ injection. Lipid accumulation and oxygen damage were less in SCO2+/− mice than those of STZ-WT. Cardiac function was preserved as well as STZ-p53KO.
Conclusions: p53 promotes fatty acid metabolism via the induction of SCO2. SCO2 increases FA oxidation, facilitates lipid accumulation and ROS production. These findings suggest that the p53-SCO2 regulatory program is maladaptive in the diabetic heart and promote lipotoxicity and contractile dysfunction.
- © 2010 by American Heart Association, Inc.