Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan.
Am J Physiol Heart Circ Physiol. 2010 Dec;299(6):H1908-16. doi: 10.1152/ajpheart.00250.2010. Epub 2010 Oct 8.
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.
生物能量动态平衡在心力衰竭中发生改变，并且可能在发病机制中发挥重要作用。p53 已被牵涉到心力衰竭中，尽管其在调节肿瘤发生中的作用已得到很好的描述，但它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 p53 诱导的糖酵解和凋亡调节剂（TIGAR）在模拟可能导致心力衰竭的缺血条件下对心肌能量代谢的作用。在心肌梗死后，p53 和 TIGAR 的表达明显上调，与野生型小鼠相比，p53 缺失型小鼠的凋亡心肌细胞减少了 42％。为了研究 p53 对能量代谢的影响，我们将心肌细胞暴露于缺氧环境中。缺氧以 p53 依赖的方式诱导 p53 和 TIGAR 的表达。p53 或 TIGAR 的敲低增加了糖酵解，使果糖-2,6-二磷酸水平升高，并减少了心肌细胞凋亡。缺氧应激降低了心肌细胞的磷酸肌酸含量和线粒体膜电位，而不改变 ATP 含量，TIGAR 的敲低可预防这些作用。通过 2-脱氧葡萄糖抑制糖酵解阻断了这些生物能量作用和 TIGAR siRNA 介导的凋亡预防作用，而相反，TIGAR 的过表达减少了葡萄糖的利用并增加了凋亡。我们的数据表明，p53 和 TIGAR 抑制缺氧心肌细胞中的糖酵解，并且抑制糖酵解与凋亡密切相关，这表明 p53 和 TIGAR 是缺血应激下细胞能量动态平衡和细胞死亡的重要介质。
