title: 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.
  
  
  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<0.01), with a marked decrease in cardiac performance. Mitochondrial oxygen consumption was increased (136% versus 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 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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Eri
authors.initials: E
authors.lastname: Iwai-Kanai
authors.forename: Masaki
authors.initials: M
authors.lastname: Kimata
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hoshino
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Nakaoka
authors.forename: Maki
authors.initials: M
authors.lastname: Katamura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Okawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Ariyoshi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Mita
authors.forename: Koji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Okigaki
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Hideo
authors.initials: H
authors.lastname: Tanaka
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Takamatsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D048909:Diabetes Complications / Q000150:complications* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008929:Mitochondria, Heart / Q000378:metabolism*; D018832:Molecular Chaperones; D032383:Myocytes, Cardiac / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013311:Streptozocin / Q000009:adverse effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; C511423:SCO2 protein, mouse; D016159:Tumor Suppressor Protein p53; D013311:Streptozocin; D003576:Electron Transport Complex IV