Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling
Inhibition of glutaminase 1-mediated glutaminolysis improves pathological cardiac remodeling
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抑制谷氨酰胺酶 1 介导的谷氨酰胺分解可改善病理性心脏重塑
DOI：
10.1152/ajpheart.00692.2021
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发表时间：
2022
影响因子：
4.8
通讯作者：
Hirata Ken-Ichi
中科院分区：
文献类型：
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作者：
Yoshikawa Sachiko;Nagao Manabu;Toh Ryuji;Shinohara Masakazu;Iino Takuya;Irino Yasuhiro;Nishimori Makoto;Tanaka Hidekazu;Satomi-Kobayashi Seimi;Ishida Tatsuro;Hirata Ken-Ichi
心脏代谢的改变与心力衰竭(HF)的发病密切相关。我们最近报道了大鼠心肌细胞中谷氨酰胺依赖的失活，称为谷氨酰胺溶解，被H_2O_2激活，这似乎是心肌细胞在急性应激中生存的一种适应性反应。然而，谷氨酰胺分解在心力衰竭的病理生理学中的分子机制和基础作用仍不清楚。在这里，我们用血管紧张素II(Ang II)处理野生型小鼠(C57BL/6J)和大鼠新生心肌细胞(RNCM)和成纤维细胞(RNCFs)，以诱导病理性心脏重构。在Ang II诱导的小鼠心脏、RNCM和RNCFs中，谷氨酰胺酶1(GLS1)是谷氨酰胺降解的限速酶。出人意料的是，GLS1抑制剂减轻了Ang II诱导的小鼠左室肥厚和纤维化，GLS1的基因敲除和药理干扰分别抑制了RNCM和RNCFs的肥大和增殖。用13C标记的谷氨酰胺对RNCMS和RNCFs进行稳定同位素示踪，观察Ang II处理的RNCMS和RNCFs的谷氨酰胺代谢通量。在两种细胞类型中，~(13)C原子对三羧酸(TCA)循环中间体及其衍生物的掺入均显著增强，表明肥厚心脏的谷氨酰胺分解被激活。值得注意的是，抑制GLS1减少了谷氨酰胺衍生的天冬氨酸和柠檬酸的产生，这是核酸和脂类生物合成所必需的，可能有助于抑制心肌肥大和纤维化。本研究的结果表明，GLS1介导的谷氨酰胺分解上调导致了不适应性心脏重塑。抑制这一逆转途径可能是治疗高血压的一种新方法。据我们所知，这项研究首次证明GLS1表达增加和随后激活的谷氨酰胺分解与心肌肥厚和纤维化的加重有关。抑制GLS1在体外和体内均可拮抗不利的心脏重构，部分原因是减少了细胞生长和增殖所必需的谷氨酰胺代谢产物。心肌细胞合成代谢反应中谷氨酰胺利用率的增加可能与HF的发生和发展有关。请收听本文在https://ajpheart.podbean.com/e/gls1-inhibition-improves-cardiac-remodeling-english-language-version/(日语版：https://ajpheart.podbean.com/e/gls1-inhibition-improves-cardiac-remodeling-japanese-language-version/))上的相应播客
Alterations in cardiac metabolism are strongly associated with the pathogenesis of heart failure (HF). We recently reported that glutamine-dependent anaplerosis, termed glutaminolysis, was activated by H2O2stimulation in rat cardiomyocytes, which seemed to be an adaptive response by which cardiomyocytes survive acute stress. However, the molecular mechanisms and fundamental roles of glutaminolysis in the pathophysiology of the failing heart are still unknown. Here, we treated wild-type mice (C57BL/6J) and rat neonatal cardiomyocytes (RNCMs) and fibroblasts (RNCFs) with angiotensin II (ANG II) to induce pathological cardiac remodeling. Glutaminase 1 (GLS1), a rate-limiting glutaminolysis enzyme, was significantly increased in ANG II-induced mouse hearts, RNCMs and RNCFs. Unexpectedly, a GLS1 inhibitor attenuated ANG II-induced left ventricular hypertrophy and fibrosis in the mice, and gene knockdown and pharmacological perturbation of GLS1 suppressed hypertrophy and the proliferation of RNCMs and RNCFs, respectively. Using mass spectrometry (MS)-based stable isotope tracing with13C-labeled glutamine, we observed glutamine metabolic flux in ANG II-treated RNCMs and RNCFs. The incorporation of13C atoms into tricarboxylic acid (TCA) cycle intermediates and their derivatives was markedly enhanced in both cell types, indicating the activation of glutaminolysis in hypertrophied hearts. Notably, GLS1 inhibition reduced the production of glutamine-derived aspartate and citrate, which are required for the biosynthesis of nucleic acids and lipids, possibly contributing to the suppression of cardiac hypertrophy and fibrosis. The findings of the present study reveal that GLS1-mediated upregulation of glutaminolysis leads to maladaptive cardiac remodeling. Inhibition of this anaplerotic pathway could be a novel therapeutic approach for HF.NEW & NOTEWORTHYTo our knowledge, this study is the first to demonstrate that increased GLS1 expression and subsequent activation of glutaminolysis are associated with exacerbation of cardiac hypertrophy and fibrosis. Inhibiting GLS1 antagonized the adverse cardiac remodeling in vitro and in vivo, partly due to reduction of glutamine-derived metabolites, which are necessary for cellular growth and proliferation. Increased glutamine utilization for anabolic reactions in cardiac cells may be related to the pathogenesis and development of HF.Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/gls1-inhibition-improves-cardiac-remodeling-english-language-version/ (Japanese version: https://ajpheart.podbean.com/e/gls1-inhibition-improves-cardiac-remodeling-japanese-language-version/)