Abstract 11403: p53 Promotes Cardiac Dysfunction in Diabetes Mellitus by Excessive Mitochondrial Respiration and Fat/cd36 Upregulation
Background: Diabetic cardiomyopathy is characterized by energetic dysregulation due to glucotoxicity, lipotoxicity and mitochondrial alterations. p53 and its downstream mitochondrial assembly protein, synthesis of cytochrome c oxidase 2 (SCO2) are important regulators of mitochondrial respiration. However, the involvement in diabetic cardiomyopathy remains to be determined.
Methods and Results: The role of p53 and SCO2 in energy metabolism was examined in both type I (streptozotocin (STZ) administration) and type II diabetic (db/db) mice. Cardiac expressions of p53 and SCO2 in 4-week STZ diabetic mice were up-regulated (185% and 152% vs. controls, respectively, p<0.01) with a marked decrease in cardiac performance. Mitochondrial oxygen consumption was increased (136% vs. control, p<0.01) in parallel with augmentation of mitochondrial cytochrome c oxidase (complex IV) activity. Reactive oxygen species (ROS)-damaged myocytes and lipid accumulation were increased in association with membrane-localization of fatty acid (FA) translocase protein FAT/CD36. Antioxidant tempol reduced the increased expressions of p53 and SCO2 in STZ-diabetic hearts, and normalized alterations in mitochondrial oxygen consumption, lipid accumulation and cardiac dysfunction. Similar results were observed in db/db mice, while the cardiac and metabolic abnormalities were prevented in p53-deficient or SCO2-deficient STZ diabetic mice. Over expression of SCO2 in cardiac myocytes increased mitochondrial ROS and FA accumulation, while knock-down of SCO2 reverted them.
Conclusion: Myocardial p53/SCO2 signal is activated by diabetes-mediated ROS generation. Those signals increase mitochondrial oxygen consumption and FAT/CD36 expression, resulting in excessive generation of mitochondria-derived ROS and lipid accumulation in association with cardiac dysfunction.
- © 2011 by American Heart Association, Inc.