| p53 promotes cardiac dysfunction in diabetic mellitus caused by excessive mitochondrial respiration-mediated reactive oxygen species generation and lipid accumulation. | |
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MedLine Citation:
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PMID: 22075967 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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<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. |
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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-11-09 |
Journal Detail:
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Title: Circulation. Heart failure Volume: 5 ISSN: 1941-3297 ISO Abbreviation: Circ Heart Fail Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-01-18 Completed Date: 2012-04-13 Revised Date: 2012-05-24 |
Medline Journal Info:
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Nlm Unique ID: 101479941 Medline TA: Circ Heart Fail Country: United States |
Other Details:
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Languages: eng Pagination: 106-15 Citation Subset: IM |
Affiliation:
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Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD36 / metabolism Diabetes Complications / complications*, metabolism Diabetes Mellitus, Experimental / chemically induced, complications*, metabolism Diabetic Cardiomyopathies / etiology*, metabolism Disease Models, Animal Electron Transport Complex IV / genetics, metabolism Fatty Acids / metabolism Lipid Metabolism / physiology* Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Mitochondria, Heart / metabolism* Myocytes, Cardiac / metabolism Oxygen Consumption / physiology Reactive Oxygen Species / metabolism* Streptozocin / adverse effects Tumor Suppressor Protein p53 / deficiency, genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD36; 0/Fatty Acids; 0/Reactive Oxygen Species; 0/Tumor Suppressor Protein p53; 18883-66-4/Streptozocin; EC 1.9.3.-/SCO2 protein, mouse; EC 1.9.3.1/Electron Transport Complex IV |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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