Critical role of glutamine metabolism in cardiomyocytes under oxidative stress
Critical role of glutamine metabolism in cardiomyocytes under oxidative stress
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DOI：
10.1016/j.bbrc.2020.11.018
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发表时间：
2021-01-01
影响因子：
3.1
通讯作者：
Hirata, Ken-ichi
中科院分区：
文献类型：
--
作者：
Watanabe, Koichi;Nagao, Manabu;Hirata, Ken-ichi
背景：心肌细胞代谢重塑与心力衰竭的发病机制密切相关。谷氨酰胺分解是一种将谷氨酰胺衍生的α-酮戊二酸(α-KG)结合到三羧酸(TCA)循环中的逆转录途径。研究目的：探讨谷氨酰胺代谢在氧化应激所致心肌衰竭中的调节机制和生物学效应。方法与结果：过氧化氢可显著降低新生大鼠心肌细胞内谷氨酰胺、谷氨酸和α-KG的水平。为了更好地了解衰竭心肌的代谢流量，我们进行了一项稳定的同位素示踪研究，发现在氧化应激下，RNCM中谷氨酰胺分解上调。与此相一致的是，在经过过氧化氢处理的RNCM中，将谷氨酰胺转化为谷氨酸的谷氨酰胺酶(GIs)的酶活性被增强。这些发现表明，在氧化应激下，心肌细胞中谷氨酰胺的修复作用增强，以补偿CKG的减少。此外，抑制GIs可降低H_2O_2刺激的RNCM的心肌细胞存活率、ATP产量和谷胱甘肽(GSH)合成。最后，我们评估了ciKG对衰竭心肌的影响，观察到α-酮戊二酸二甲酯(DMKG)可能通过提高细胞内ATP和GSH水平来抑制氧化应激诱导的细胞死亡。结论：我们的研究表明，在氧化应激下，谷氨酰胺分解被上调，以补偿αKG的丢失和它在TCA循环中的补充，从而通过维持ATP和GSH水平来发挥心脏保护作用。心脏衰竭时谷氨酰胺代谢的调节可能为心衰的治疗提供新的策略。(C)2020 Elsevier Inc.保留所有权利。
Background: Metabolic remodeling in cardiomyocytes is deeply associated with the pathogenesis of heart failure (HF). Glutaminolysis is an anaplerotic pathway that incorporates alpha-ketoglutarate (alpha KG) derived from glutamine into the tricarboxylic acid (TCA) cycle. It is well known that cancer cells depend on glutamine for their increased energy demand and proliferation; however, the physiological roles of glutamine metabolism in failing hearts remain unclear.Objective: To investigate the regulatory mechanisms and biological effects of glutamine metabolism in oxidative stress-induced failing myocardium.Methods and results: The intracellular levels of glutamine, glutamate, and alpha KG were significantly decreased by H2O2 stimulation in rat neonatal cardiomyocytes (RNCMs). To better understand the metabolic flux in failing myocardium, we performed a stable isotope tracing study and found that glutaminolysis was upregulated in RNCMs under oxidative stress. Consistent with this, the enzymatic activity of glutaminase (GIs), which converts glutamine to glutamate, was augmented in RNCMs treated with H2O2. These findings suggest that glutamine anaplerosis is enhanced in cardiomyocytes under oxidative stress to compensate for the reduction of ciKG. Furthermore, the inhibition of GIs reduced cardiac cell viability, ATP production, and glutathione (GSH) synthesis in RNCMs with H2O2 stimulation. Finally, we evaluated the effects of ciKG on failing myocardium and observed that dimethyl alpha-ketoglutarate (DMKG) suppressed oxidative stress-induced cell death likely due to the enhancement of intracellular ATP and GSH levels.Conclusion: Our study demonstrates that under oxidative stress, glutaminolysis is upregulated to compensate for the loss of alpha KG and its replenishment into the TCA cycle, thereby exerting cardioprotective effects by maintaining ATP and GSH levels. Modulation of glutamine metabolism in failing hearts might provide a new therapeutic strategy for HF. (C) 2020 Elsevier Inc. All rights reserved.