Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart
Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart
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DOI：
10.1016/j.yjmcc.2015.02.021
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发表时间：
2015-05-01
影响因子：
5
通讯作者：
Sano, Motoaki
中科院分区：
文献类型：
--
作者：
Matsuhashi, Tomohiro;Hishiki, Takako;Sano, Motoaki
二氯乙酸（DCA）通过抑制丙酮酸脱氢酶（PDH）激酶促进丙酮酸进入克雷布斯循环，从而使PDH保持在活性去磷酸化状态。DCA作为一种潜在的代谢靶向治疗心力衰竭的药物最近受到了关注，但DCA在心脏中治疗作用的分子基础仍然是一个谜。每日一次口服DCA可减轻压力超负荷诱导的左心室重构。我们研究了通过DCA的代谢干预进入克雷布斯循环的丙酮酸碳（来自葡萄糖）的代谢命运的变化。C-13（6）-葡萄糖通路追踪分析显示，在对照和压力超负荷心脏中，DCA介导的PDH去磷酸化导致乙酰辅酶A库增加，而不是在线粒体中完全氧化以产生ATP。DCA以剂量依赖性方式诱导组蛋白H3 K9和H4的过度乙酰化，与培养的心肌细胞中PDH的去磷酸化平行。DCA施用增加体内小鼠心脏中的组蛋白H3 K9乙酰化。有趣的是，DCA依赖的组蛋白乙酰化与23%的基因（23，474个基因中的545个）的上调相关。基因本体分析表明，这些基因是高度丰富的转录相关类别。这一证据表明，持续激活PDH的DCA导致过量生产的乙酰辅酶A，这超过了在克雷布斯循环中的氧化，并导致组蛋白乙酰化。我们认为，DCA介导的PDH激活有可能诱导心脏的表观遗传重构，这至少部分地形成了DCA在心脏中的治疗作用的分子基础。(C)2015爱思唯尔有限公司版权所有。
Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. C-13(6)-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 23% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart. (C) 2015 Elsevier Ltd. All rights reserved.