| p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic stress. | |
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MedLine Citation:
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PMID: 20935145 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Bioenergetic homeostasis is altered in heart failure and may play an important role in pathogenesis. p53 has been implicated in heart failure, and although its role in regulating tumorigenesis is well characterized, its activities on cellular metabolism are just beginning to be understood. We investigated the role of p53 and its transcriptional target gene TP53-induced glycolysis and apoptosis regulator (TIGAR) in myocardial energy metabolism under conditions simulating ischemia that can lead to heart failure. Expression of p53 and TIGAR was markedly upregulated after myocardial infarction, and apoptotic myocytes were decreased by 42% in p53-deficient mouse hearts compared with those in wild-type mice. To examine the effect of p53 on energy metabolism, cardiac myocytes were exposed to hypoxia. Hypoxia induced p53 and TIGAR expression in a p53-dependent manner. Knockdown of p53 or TIGAR increased glycolysis with elevated fructose-2,6-bisphosphate levels and reduced myocyte apoptosis. Hypoxic stress decreased phosphocreatine content and the mitochondrial membrane potential of myocytes without changes in ATP content, the effects of which were prevented by the knockdown of TIGAR. Inhibition of glycolysis by 2-deoxyglucose blocked these bioenergetic effects and TIGAR siRNA-mediated prevention of apoptosis, and, in contrast, overexpression of TIGAR reduced glucose utilization and increased apoptosis. Our data demonstrate that p53 and TIGAR inhibit glycolysis in hypoxic myocytes and that inhibition of glycolysis is closely involved in apoptosis, suggesting that p53 and TIGAR are significant mediators of cellular energy homeostasis and cell death under ischemic stress. |
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Authors:
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Masaki Kimata; Satoaki Matoba; Eri Iwai-Kanai; Hideo Nakamura; Atsushi Hoshino; Mikihiko Nakaoka; Maki Katamura; Yoshifumi Okawa; Yuichiro Mita; Mitsuhiko Okigaki; Koji Ikeda; Tetsuya Tatsumi; Hiroaki Matsubara |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-08 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 299 ISSN: 1522-1539 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-03 Completed Date: 2011-01-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1908-16 Citation Subset: IM |
Affiliation:
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Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Animals Apoptosis Apoptosis Regulatory Proteins / genetics, metabolism* Cell Hypoxia Cells, Cultured Deoxyglucose / metabolism Disease Models, Animal Energy Metabolism* Glycolysis Homeostasis Membrane Potential, Mitochondrial Mice Mice, Knockout Myocardial Infarction / genetics, metabolism*, pathology Myocytes, Cardiac / metabolism*, pathology Phosphocreatine / metabolism Phosphofructokinase-2 / metabolism Proteins / genetics, metabolism* RNA Interference Rats Stress, Physiological* Time Factors Transfection Tumor Suppressor Protein p53 / deficiency, genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Apoptosis Regulatory Proteins; 0/Proteins; 0/TIGAR protein, mouse; 0/Tumor Suppressor Protein p53; 154-17-6/Deoxyglucose; 56-65-5/Adenosine Triphosphate; 67-07-2/Phosphocreatine; EC 2.7.1.105/Phosphofructokinase-2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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