p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic stress
p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic stress
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DOI：
10.1152/ajpheart.00250.2010
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发表时间：
2010-12-01
影响因子：
4.8
通讯作者：
Matsubara, Hiroaki
中科院分区：
文献类型：
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作者：
Kimata, Masaki;Matoba, Satoaki;Matsubara, Hiroaki
[10] Kimata M，Matoba S，Iwai-Kanai E，中村H，Hoshino A，Nakaoka M，Katamura M，Okawa Y，Mita Y，Okigaki M，Ikeda K，Tatsumi T，Matsubara H. p53和TIGAR调节缺氧应激下心肌细胞能量稳态。Am J Physiol Heart Circ Physiol 299：H1908-H1916，2010.首次发表于2010年10月8日; doi：10.1152/ajpheart.00250.2010.-心力衰竭时生物能量稳态改变，可能在发病机制中起重要作用。p53与心力衰竭有关，尽管其在调节肿瘤发生中的作用已被充分表征，但其对细胞代谢的活性才刚刚开始被理解。我们研究了p53及其转录靶基因TP 53诱导的糖酵解和凋亡调节因子（TIGAR）在心肌能量代谢中的作用，在模拟缺血的条件下，可导致心力衰竭。心肌梗死后p53和TIGAR的表达显著上调，与野生型小鼠相比，p53缺陷小鼠心脏中凋亡的心肌细胞减少了42%。为了检测p53对能量代谢的影响，将心肌细胞暴露于缺氧。缺氧诱导p53和TIGAR表达的p53依赖的方式。p53或TIGAR的敲除增加糖酵解，升高果糖-2，6-二磷酸水平，减少心肌细胞凋亡。低氧应激降低磷酸肌酸含量和心肌细胞的线粒体膜电位而不改变ATP含量，其影响被TIGAR的敲低所阻止。通过2-脱氧葡萄糖抑制糖酵解阻断了这些生物能量效应和TIGAR siRNA介导的细胞凋亡预防，相反，TIGAR的过表达降低了葡萄糖利用并增加了细胞凋亡。我们的数据表明，p53和TIGAR抑制糖酵解在缺氧的心肌细胞和糖酵解的抑制密切参与细胞凋亡，表明p53和TIGAR是重要的介质的细胞能量稳态和细胞死亡缺血应激。
Kimata M, Matoba S, Iwai-Kanai E, Nakamura H, Hoshino A, Nakaoka M, Katamura M, Okawa Y, Mita Y, Okigaki M, Ikeda K, Tatsumi T, Matsubara H. p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic stress. Am J Physiol Heart Circ Physiol 299: H1908-H1916, 2010. First published October 8, 2010; doi:10.1152/ajpheart.00250.2010.-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.