GLS1-Mediated Redundancy in Glutamate Accelerates Arterial Calcification via Activating NMDAR/Ca(2+)/β-Catenin Pathway.

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(2+) 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(2+) influx, which in turn exacerbates β-Catenin-regulated osteogenic reprogramming in VSMCs.