Abstract 3953: p53 Promotes Heart Failure With Lipid Accumulation in Diabetes
Background: Altered myocardial metabolism is an important contributor to the development of diabetic cardiomyopathy. We have demonstrated mitochondrial respiration is regulated by p53 via SCO2 (Synthesis of cytochrome c oxidase 2), which leads to a profound reduction in exercise capacity of p53 deficient mice (p53KO). However, the role of p53 in diabetic heart is unknown.
Methods and Results: The role of p53 in the development of diabetic cardiomyopathy was examined in both type I (streptozotocin (STZ) administration), and type II diabetes (db/db mice). In both models, cardiac contraction was declined and p53 protein in the heart was induced markedly (db/db mice at 10 weeks old, 4 weeks after the injection of STZ). To clarify the role of p53, we made STZ induced diabetes model with p53KO. Although the blood glucose level, lipid profile, and gene expression of PPARalfa, PGC1alfa and CD36 were similar in wild type mice (WT) and p53KO, cardiac contractile function was preserved significantly in p53KO. There was no difference of the number of apoptotic myocytes, CD31 positive cells or fibrosis in both mice. However, we found oxygen consumption of isolated heart mitochondria was increased and mitochondrial complex IV activity was up-regulated dramatically in WT. Accumulation of lipid deposits and the number of myocytes stained with 8-OHdG were significantly increased in WT than those of p53KO. To investigate the role of p53 on mitochondria, we induced p53 protein or SCO2 protein in the myocytes. p53 or SCO2 augments uptake of oleic acid and palmitic acid significantly. Those lipids were accumulated in myocytes, too. Generation of reactive oxygen species (ROS) detected by MitoSOX™ were also augmented. However, these alterations were eliminated by the knock down of SCO2. Furthermore, we induced diabetes with SCO2+/− mice by STZ injection. Lipid accumulation and oxygen damage were less in SCO2 +/− mice than those of WT. Cardiac function was preserved as well as p53KO.
Conclusion: p53, induced in the diabetic heart, pronounced fatty acid uptake and accumulation via the induction of SCO2. These changes of cardiac metabolism promote not only the lipid accumulation, but also the ROS production. Finally, p53 augments lipotoxicity and accelerates cardiac damage in diabetes.