p53 Promotes Cardiac Dysfunction in Diabetic Mellitus Caused by Excessive Mitochondrial Respiration-Mediated Reactive Oxygen Species Generation and Lipid Accumulation

Abstract

Background-Diabetic cardiomyopathy is characterized by energetic dysregulation caused by 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, whereas 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 upregulated (185% and 152% versus controls, respectively, PϽ0.01), with a marked decrease in cardiac performance. Mitochondrial oxygen consumption was increased (136% versus control, PϽ0.01) 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 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, whereas in p53-deficient or SCO2-deficient diabetic mice, the cardiac and metabolic abnormalities were prevented. Overexpression of SCO2 in cardiac myocytes increased mitochondrial ROS and fatty acid accumulation, whereas knockdown of SCO2 ameliorated them. Conclusions-Myocardial p53/SCO2 signal is activated by diabetes-mediated ROS generation to increase mitochondrial oxygen consumption, resulting in excessive generation of mitochondria-derived ROS and lipid accumulation in association with cardiac dysfunction. (Circ Heart Fail. 2012;5:106-115.)Key Words: cardiomyopathy Ⅲ diabetes mellitus Ⅲ metabolism Ⅲ heart failure Ⅲ free radicals Ⅲ mitochondria D iabetic cardiomyopathy is one of the leading causes of increased morbidity and mortality in the patients with diabetes mellitus. 1,2 Although the pathogenesis of this cardiac contractile dysfunction is still unclear, an involvement of increased reactive oxygen species (ROS) production 3 and altered mitochondrial function 4,5 have been reported. Mitochondrial uncoupling was shown to be a possible mechanism to reduce cardiac efficiency in type 2 diabetes models 6 but not in type 1 diabetes models. 7 Recent study using positron emission tomography in patients with type 1 diabetes mellitus has revealed the Clinical Perspective on p 115increased oxygen consumption and altered fatty acid (FA) metabolism. 8 These human and animal studies have shown that increased oxidative stress correlates with lipid overload, Received February 9, 2011; accepted October 31, 2011. From the Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan (H.N., S.M., E.I.-K., M. Kimata, A.H., M. Katamura, Y.O., M.A., Y.M., K.I....

Deficiency of a Lipid Droplet Protein, Perilipin 5, Suppresses Myocardial Lipid Accumulation, Thereby Preventing Type 1 Diabetes-Induced Heart Malfunction

“…On the other hand, the MCAD level in diabetic mice was comparable to that of nondiabetic mice of either genotype. Several previous papers reported that the mitochondrial electron transport chain is one of the major sites of ROS generation in the diabetic heart, contributing to heart malfunction (25)(26)(27)35). In contrast, other reports show that progression of diabetes does not affect the capacity of ROS generation by mitochondria (39,40).…”

“…Several previous studies suggested that elevation of oxidative stress in the diabetic heart is a factor contributing to the development and progression of diabetic cardiomyopathy (17,26,35). Therefore, we examined whether the diabetes-induced increase in oxidative stress is suppressed by Plin5 deficiency by measuring MDA, a derivative of lipid peroxide (Fig.…”

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

“…In addition, it is known that hyperglycemia activates p53-mediated cell death in myocytes (37). p53 also promotes cardiac dysfunction in diabetic mice (115). However, p53 has a broad functional role in cells and regulates other processes, including autophagy.…”

Mechanisms of Lipotoxicity in the Cardiovascular System

“…This protection was associated with a decrease in myocardial lipid accumulation and complex IV induction [79]. Interestingly, pressure overload itself can lead to p53-mediated activation of the inflammatory response in adipose tissue, suggesting an interesting cross talk between the heart and peripheral adipose tissue metabolism [80••, 81••].…”