ATP-binding cassette transporter A1 (ABCA1) is an essential regulator of intracellular cholesterol efflux. Secreted cholesterol binds to lipid-free apolipoprotein A-I (apoA-I) in peripheral blood to constitute high-density lipoprotein cholesterol (HDL) complexes. ABCA1 protein on the surface of macrophages acts as a crucial controller in preventing cholesterol accumulation. Importantly, ABCA1 is unstable and easily degraded via a series of biochemical activities, including but not limited to calpain-mediated and ubiquitin-proteasome system-mediated processes. How accelerated ABCA1 degradation impacts disordered lipid metabolism in macrophages and foam cell formation is unclear. N-methyl d-aspartate receptors (NMDARs) are ionotropic glutamate receptors with high calcium permeability. Calcium influx via NMDARs activates downstream signaling pathways. Over-activation of NMDARs stimulated by NMDA contributes to dysfunctional lipid metabolism in macrophages and foam cell formation via promotion of calpain-mediated ABCA1 proteolysis. However, increased NMDAR activity does not affect liver X receptor expression or ABCA1 mRNA levels. Following NMDA receptor silencing or calpain inhibition, NMDA treatment did not reduce ABCA1 protein levels, nor caused lipid accumulation in macrophages. In addition, NMDAR over-activation activates NF-κB signaling to promote IL-1β and IL-6 macrophage marker expression. However, NMDAR silencing and calpain inhibition reduce inflammatory macrophage responses. In summary, our study suggests that NMDAR activation reduces surface ABCA1 protein, promotes lipid accumulation, and induces the production and secretion of many inflammatory mediators in macrophages, possibly through enhanced calpain-mediated ABCA1 protein degradation. Thus, the NMDAR receptor may be a novel pharmacologic target for atherosclerosis therapy.

ATP结合盒转运蛋白A1（ABCA1）是细胞内胆固醇外流的重要调节剂。分泌的胆固醇与外周血中的无脂载脂蛋白AI（apoA-I）结合，构成高密度脂蛋白胆固醇（HDL）复合物。巨噬细胞表面的ABCA1蛋白可作为防止胆固醇蓄积的关键控制器。重要的是，ABCA1不稳定且容易通过一系列生化活性降解，包括但不限于钙蛋白酶介导的和泛素-蛋白酶体系统介导的过程。尚不清楚加速的ABCA1降解如何影响巨噬细胞中脂质代谢紊乱和泡沫细胞形成。N一甲基d-天冬氨酸受体（NMDAR）是具有高钙渗透性的离子型谷氨酸受体。经由NMDAR的钙流入激活了下游信号通路。NMDA刺激的NMDARs过度活化通过促进钙蛋白酶介导的ABCA1蛋白水解作用，导致巨噬细胞脂质代谢功能异常和泡沫细胞形成。但是，增加的NMDAR活性不会影响肝X受体表达或ABCA1 mRNA水平。NMDA受体沉默或抑制钙蛋白酶后，NMDA处理未降低ABCA1蛋白水平，也未引起巨噬细胞脂质蓄积。此外，NMDAR过度激活会激活NF-κB信号传导，从而促进IL-1β和IL-6巨噬细胞标志物的表达。但是，NMDAR沉默和钙蛋白酶抑制减少炎症巨噬细胞反应。综上所述，我们的研究表明，NMDAR激活可减少表面ABCA1蛋白，促进脂质蓄积并诱导巨噬细胞中许多炎症介质的产生和分泌，这可能是由于钙蛋白酶介导的ABCA1蛋白降解增强所致。因此，NMDAR受体可能是动脉粥样硬化治疗的新型药理靶标。