1. p53 promotes cardiac dysfunction in diabetic mellitus caused by excessive mitochondrial respiration-mediated reactive oxygen species generation and lipid accumulation
- Author
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Koji Ikeda, Satoaki Matoba, Yoshifumi Okawa, Eri Iwai-Kanai, Yuichiro Mita, Mikihiko Nakaoka, Atsushi Hoshino, Hideo Tanaka, Maki Katamura, Hiroaki Matsubara, Tetsuro Takamatsu, Makoto Ariyoshi, Hideo Nakamura, Souichi Adachi, Masaki Kimata, and Mitsuhiko Okigaki
- Subjects
Mitochondrial ROS ,CD36 Antigens ,Male ,medicine.medical_specialty ,Diabetic Cardiomyopathies ,CD36 ,Mitochondrion ,Mitochondria, Heart ,Streptozocin ,Diabetes Mellitus, Experimental ,Diabetes Complications ,Electron Transport Complex IV ,Mice ,Oxygen Consumption ,Internal medicine ,Diabetic cardiomyopathy ,Medicine ,Cytochrome c oxidase ,Animals ,Myocytes, Cardiac ,Heart metabolism ,chemistry.chemical_classification ,Mice, Knockout ,Reactive oxygen species ,biology ,business.industry ,Fatty Acids ,medicine.disease ,Lipid Metabolism ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Lipotoxicity ,biology.protein ,Tumor Suppressor Protein p53 ,Cardiology and Cardiovascular Medicine ,business ,Reactive Oxygen Species ,Molecular Chaperones - 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, P P 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.
- Published
- 2011