Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Division of Evidence-based Laboratory Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Biochem Biophys Res Commun. 2021 Jan 1;534:687-693. doi: 10.1016/j.bbrc.2020.11.018. Epub 2020 Nov 17.
Metabolic remodeling in cardiomyocytes is deeply associated with the pathogenesis of heart failure (HF). Glutaminolysis is an anaplerotic pathway that incorporates α-ketoglutarate (αKG) 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.
To investigate the regulatory mechanisms and biological effects of glutamine metabolism in oxidative stress-induced failing myocardium.
The intracellular levels of glutamine, glutamate, and αKG were significantly decreased by HO 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 (Gls), which converts glutamine to glutamate, was augmented in RNCMs treated with HO. These findings suggest that glutamine anaplerosis is enhanced in cardiomyocytes under oxidative stress to compensate for the reduction of αKG. Furthermore, the inhibition of Gls reduced cardiac cell viability, ATP production, and glutathione (GSH) synthesis in RNCMs with HO stimulation. Finally, we evaluated the effects of αKG on failing myocardium and observed that dimethyl α-ketoglutarate (DMKG) suppressed oxidative stress-induced cell death likely due to the enhancement of intracellular ATP and GSH levels.
Our study demonstrates that under oxidative stress, glutaminolysis is upregulated to compensate for the loss of αKG 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.
心肌细胞的代谢重塑与心力衰竭（HF）的发病机制密切相关。谷氨酰胺分解代谢是一种生酮作用途径，可将来自谷氨酰胺的α-酮戊二酸（αKG）纳入三羧酸（TCA）循环。众所周知，癌细胞依赖谷氨酰胺来满足其增加的能量需求和增殖；然而，谷氨酰胺代谢在衰竭心脏中的生理作用仍不清楚。
研究谷氨酰胺代谢在氧化应激诱导的衰竭心肌中的调节机制和生物学效应。
HO 刺激可使大鼠乳鼠心肌细胞（RNCMs）中的谷氨酰胺、谷氨酸和 αKG 细胞内水平显著降低。为了更好地了解衰竭心肌中的代谢通量，我们进行了稳定同位素示踪研究，发现氧化应激下 RNCMs 中的谷氨酰胺分解代谢上调。与此一致，HO 处理的 RNCMs 中谷氨酰胺酶（Gls）的酶活性增强，Gls 将谷氨酰胺转化为谷氨酸。这些发现表明，氧化应激下心肌细胞中的谷氨酰胺同化作用增强，以补偿 αKG 的减少。此外，Gls 抑制可降低 HO 刺激的 RNCMs 的心肌细胞活力、ATP 产生和谷胱甘肽（GSH）合成。最后，我们评估了αKG 对衰竭心肌的影响，观察到二甲基-α-酮戊二酸（DMKG）抑制氧化应激诱导的细胞死亡，可能是由于细胞内 ATP 和 GSH 水平的提高。
本研究表明，在氧化应激下，谷氨酰胺分解代谢上调以补偿αKG 的损失及其对 TCA 循环的补充，从而通过维持 ATP 和 GSH 水平发挥心脏保护作用。衰竭心脏中谷氨酰胺代谢的调节可能为 HF 提供一种新的治疗策略。
