Zhou Ziting, Dong Bing, He Dayu, Ma Jianshuai, Kong Yun, Zhu Huijin, Xie Chen, Yang Tiecheng, Zhen Xin, Zhang Zhengzhipeng, He Zhaohui, Cheng Jinkun, Huang Aoran, Chen Jie, Wu Ruo, Yin Huiyong, Chen Yanlian, Tao Jun, Huang Hui
Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518033, China.
Medical Research Center, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518033, China.
Adv Sci (Weinh). 2025 Jun;12(21):e2414252. doi: 10.1002/advs.202414252. Epub 2025 Apr 28.
Arterial calcification is a powerful predictor of both the events and mortality associated with cardiovascular diseases in chronic kidney disease (CKD) patients. GLS1 (glutaminase 1), a rate-limiting enzyme catalyzing the conversion of glutamine to glutamate, is disordered in various cardiovascular diseases. However, the potential interplay between GLS1-mediated glutamate production and arterial calcification remains poorly understood. Here, LC-MS/MS analysis of CKD patients' samples shows an abnormally elevated activity of GLS1, reflected by the increased glutamate/glutamine ratio. Moreover, GLS1 activity is positively correlated with arterial calcification progression, and its expression is upregulated in calcified arteries. Treatment with GLS1 inhibitors or knockdown of GLS1 alleviates osteogenic reprogramming. In contrast, glutamate administration boosts the development of arterial calcification. Mechanistically, GLS1 redundancy-regulated glutamate superfluity stimulates the activation of N-methyl-d-aspartate receptors (NMDAR), leading to Ca influx and extracellular regulated protein kinases (ERK) phosphorylation, followed by the nuclear translocation of β-Catenin and acceleration of osteogenic reprogramming of vascular smooth muscle cells (VSMCs) in further. This research defines GLS1 as a key contributor to arterial calcification. Glutamate, a major product of GLS1-mediated glutamine metabolism, exerts a deleterious effect on arterial calcification by activating NMDAR and subsequently triggering Ca influx, which in turn exacerbates β-Catenin-regulated osteogenic reprogramming in VSMCs.
动脉钙化是慢性肾脏病（CKD）患者发生心血管疾病相关事件及死亡的有力预测指标。谷氨酰胺酶1（GLS1）是催化谷氨酰胺转化为谷氨酸的限速酶，在多种心血管疾病中功能紊乱。然而，GLS1介导的谷氨酸生成与动脉钙化之间的潜在相互作用仍知之甚少。本文通过液相色谱-串联质谱（LC-MS/MS）分析CKD患者样本发现，谷氨酸/谷氨酰胺比值升高反映出GLS1活性异常升高。此外，GLS1活性与动脉钙化进展呈正相关，且其在钙化动脉中的表达上调。使用GLS1抑制剂或敲低GLS1可减轻成骨重编程。相反，给予谷氨酸会促进动脉钙化发展。机制上，GLS1冗余调节的谷氨酸过剩刺激N-甲基-D-天冬氨酸受体（NMDAR）激活，导致钙离子内流和细胞外调节蛋白激酶（ERK）磷酸化，随后β-连环蛋白核转位，进而加速血管平滑肌细胞（VSMC）的成骨重编程。本研究确定GLS1是动脉钙化的关键促成因素。谷氨酸作为GLS介导的谷氨酰胺代谢的主要产物，通过激活NMDAR并随后触发钙离子内流，对动脉钙化产生有害影响，进而加剧β-连环蛋白调节的VSMC成骨重编程。
