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

• DOI: 10.1161/circheartfailure.111.961565
• Publication Date: 2011-11-10T06:30:44Z
• Authors: Hideo Nakamura; Satoaki Matoba; Eri Iwai-Kanai; Masaki Kimata; Atsushi Hoshino; Mikihiko Nakaoka; Maki Katamura; Yoshifumi Okawa; Makoto Ariyoshi; Yuichiro Mita; Koji Ikeda; Mitsuhiko Okigaki; Souichi Adachi; Hideo Tanaka; Tetsuro Takamatsu; Hiroaki Matsubara
• Keywords: Diabetic Cardiomyopathy; Lipotoxicity; Mitochondrial ROS; CD36

Background— Diabetic cardiomyopathy is characterized by energetic dysregulation caused glucotoxicity, lipotoxicity, and mitochondrial alterations. p53 its downstream assembly protein, synthesis of cytochrome c oxidase 2 (SCO2), are important regulators respiration, whereas the involvement in diabetic remains to be determined. Methods Results— The role SCO2 energy metabolism was examined both type I (streptozotocin [STZ] administration) II ( db/db ) mice. Cardiac expressions 4-week STZ mice were upregulated (185% 152% versus controls, respectively, P <0.01), with a marked decrease cardiac performance. Mitochondrial oxygen consumption increased (136% control, <0.01) parallel augmentation (complex IV) activity. Reactive species (ROS)-damaged myocytes lipid accumulation association membrane-localization fatty acid translocase protein FAT/CD36. Antioxidant tempol reduced STZ-diabetic hearts normalized alterations consumption, accumulation, dysfunction. Similar results observed mice, p53-deficient or SCO2-deficient metabolic abnormalities prevented. Overexpression ROS knockdown ameliorated them. Conclusions— Myocardial p53/SCO2 signal activated diabetes-mediated generation increase resulting excessive mitochondria-derived