Glutamine Metabolism: a Metabolic Hub Linking Vascular Remodeling and Plaque Stability in Atherosclerosis

Atherosclerosis (AS), the pathological basis of atherosclerotic cardiovascular disease (ASCVD), is a chronic, progressive inflammatory disease whose major clinical events are primarily caused by plaque rupture and subsequent thrombosis. Plaque stability is critically dependent on vascular remodeling and dynamic extracellular matrix (ECM) remodeling. Accumulating evidence suggests that metabolic reprogramming is a key regulator of vascular cell phenotypic transitions and plaque progression. Among various metabolic pathways, glutamine (Gln) metabolism is of particular interest because it links nutrient availability with vascular cell function through carbon and nitrogen supply, maintenance of redox homeostasis, and generation of metabolites involved in epigenetic regulation. However, the contribution of Gln metabolism to AS progression remains incompletely understood. This review summarizes current advances in Gln metabolism and discusses its regulatory roles in vascular remodeling and plaque stability, with a focus on its implications for AS pathogenesis and therapeutic strategies.

Metabolomic, single-cell sequencing, and spatial transcriptomic studies have identified the role of Gln metabolism in regulating the functions of multiple vascular cell types, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), macrophages, and fibroblasts/myofibroblasts. Through glutaminolysis, Gln generates α-ketoglutarate (α-KG) to replenish the tricarboxylic acid (TCA) cycle, thereby influencing cellular proliferation, migration, inflammatory responses, and ECM remodeling. Furthermore, α-KG serves as an essential cofactor for α-KG-dependent dioxygenases, linking glutamine metabolism to epigenetic regulation through DNA and histone demethylation, ultimately influencing cell fate determination and pathological phenotypic switching. Glutamine metabolism may serve as an important metabolic regulator of vascular remodeling and plaque stability by linking metabolic, inflammatory, and epigenetic pathways. Targeting glutamine metabolism may represent a promising therapeutic strategy for stabilizing atherosclerotic plaques and preventing cardiovascular events. Further studies integrating multi-omics approaches and mechanistic validation are warranted to facilitate the clinical translation of glutamine metabolism-based interventions in AS.