N-Methyl-D-aspartate receptors: structure, signaling and roles in atherosclerosis

Atherosclerosis, a chronic inflammatory disease of the arterial wall, is a leading cause of cardiovascular diseases worldwide. The complex pathogenesis of atherosclerosis involves genetic predisposition, environmental factors, and immune responses. N-Methyl-d-aspartate receptors (NMDARs), a subclass of glutamate receptors, are critical for synaptic plasticity, learning, and memory in the central nervous system (CNS). Non-neuronal NMDARs are poorly understood compared to neuronal receptors, but there is a developing consensus that they have distinct structural and functional properties when activated by glutamate and NMDARs co-agonists. Emerging evidence indicates that non-neuronal NMDARs may participate in an array of physiological and pathophysiological processes, including but not limited to driving macrophage polarization, lipid dysregulation in macrophages, inflammation response, vascular smooth muscle cells phenotype switching and endothelial dysfunction, thereby fueling atherogenesis. This review discusses the association between NMDARs genes and atherosclerosis risk, molecular mechanisms underlying NMDARs-mediated regulation of atherosclerosis-related cells, and potential therapeutic implications. Besides, we introduce some pharmacological tools that can be used for studying NMDARs outside the CNS, which reflect modern subunit-selective agents to provide more precise insight into NMDARs mediate the various effects. Overall, the study of NMDARs may provide insights into the pathogenesis of atherosclerosis and lead to the development of more effective therapeutic strategies.