Metabolomic profiling of the heart during acute ischemic preconditioning reveals a role for SIRT1 in rapid cardioprotective metabolic adaptation.
Metabolomic profiling of the heart during acute ischemic preconditioning reveals a role for SIRT1 in rapid cardioprotective metabolic adaptation.
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DOI：
10.1016/j.yjmcc.2015.09.008
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发表时间：
2015-11
影响因子：
5
通讯作者：
Brookes PS
中科院分区：
文献类型：
--
作者：
Nadtochiy SM;Urciuoli W;Zhang J;Schafer X;Munger J;Brookes PS
缺血预适应(IPC)保护心脏等组织免受长时间的缺血再灌注(IR)损伤。我们先前已经证明，赖氨酸脱乙酰基酶SIRT1是急性IPC所必需的，并且有许多代谢靶点。虽然已经知道在IPC过程中代谢会发生改变，但潜在的代谢调节机制尚不清楚，包括SIRT1的相对重要性。因此，我们试图测试这一假设，即在IPC中发生的一些代谢适应可能需要SIRT1作为调节介质。利用体外灌流和活体小鼠心脏，基于LC-MS/MS的代谢组学和13C标记底物示踪，我们发现急性IPC改变了几种代谢途径，包括：(I)糖酵解的刺激，(Ii)糖原和几种氨基酸的合成，(Iii)还原型谷胱甘肽水平的增加，(Iv)体内代谢产物2-羟基戊二酸的升高，以及(V)抑制脂肪酸依赖的呼吸。当SIRT1被SIRT1强烈抑制时，大部分(83%)IPC引起的代谢改变被消融，主成分分析表明，当SIRT1被抑制时，IPC引起的代谢变化在本质上是不同的。此外，通过从灌流液中去除葡萄糖，同时通过燃烧脂肪维持正常的心脏功能，IPC的保护益处被取消，因此表明急性IPC需要葡萄糖依赖。综上所述，这些数据表明SIRT1信号是急性IPC快速心脏保护性代谢适应所必需的。
Ischemic preconditioning (IPC) protects tissues such as the heart from prolonged ischemia-reperfusion (IR) injury. We previously showed that the lysine deacetylase SIRT1 is required for acute IPC, and has numerous metabolic targets. While it is known that metabolism is altered during IPC, the underlying metabolic regulatory mechanisms are unknown, including the relative importance of SIRT1. Thus, we sought to test the hypothesis that some of the metabolic adaptations that occur in IPC may require SIRT1 as a regulatory mediator. Using both ex-vivo-perfused and in-vivo mouse hearts, LC-MS/MS based metabolomics and 13C-labeled substrate tracing, we found that acute IPC altered several metabolic pathways including: (i) stimulation of glycolysis, (ii) increased synthesis of glycogen and several amino acids, (iii) increased reduced glutathione levels, (iv) elevation in the oncometabolite 2-hydroxyglutarate, and (v) inhibition of fatty-acid dependent respiration. The majority (83%) of metabolic alterations induced by IPC were ablated when SIRT1 was acutely inhibited with splitomicin, and a principle component analysis revealed that metabolic changes in response to IPC were fundamentally different in nature when SIRT1 was inhibited. Furthermore, the protective benefit of IPC was abrogated by eliminating glucose from perfusion media while sustaining normal cardiac function by burning fat, thus indicating that glucose dependency is required for acute IPC. Together, these data suggest that SIRT1 signaling is required for rapid cardioprotective metabolic adaptation in acute IPC.