GLS2 links glutamine metabolism and atherosclerosis by remodeling artery walls

Abstract

Metabolic dysregulation, including perturbed glutamine–glutamate homeostasis, is common among patients with cardiovascular diseases, but the underlying mechanisms remain largely unknown. Using the human MESA cohort, here we show that plasma glutamine–glutamate ratio is an independent risk factor for carotid plaque progression. Mice deficient in glutaminase-2 (Gls2), the enzyme that mediates hepatic glutaminolysis, developed accelerated atherosclerosis and susceptibility to catastrophic cardiac events, while Gls2 overexpression partially protected from disease progression. High-throughput transcriptional profiling and high-resolution structural biology imaging of aortas showed that Gls2 deficiency perturbed extracellular matrix composition and increased vessel stiffness. This results from an imbalance of glutamine- and glutamate-dependent cross-linked proteins within atherosclerotic lesions and cellular remodeling of plaques. Thus, hepatic glutaminolysis functions as a potent regulator of glutamine homeostasis, which affects the aortic wall structure during atherosclerotic plaque progression. Murcy et al. show that increasing the plasma glutamine-to-glutamate ratio in atherosclerosis can distally reprogram transcriptional and post-transcriptional remodeling of the aorta by GLS2-dependent hepatic glutaminolysis.