Yang Ying, Lian Yi-Tian, Huang Shi-Yuan, Yang Yong, Cheng Long-Xian, Liu Kun
Department of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Cell Physiol Biochem. 2014;33(4):1117-29. doi: 10.1159/000358681. Epub 2014 Apr 9.
γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, acts on GABA receptors to play an important role in the modulation of macrophage functions. The present study examined the effects of GABA and a GABA receptor agonist on modulating cholesterol-metabolism-associated molecules in human monocyte-derived macrophages (HMDMs).
ORO stain, HPLC, qRT-PCR, Western blot and EMSA were carried out using HMDMs exposed to ox-LDL with or without GABAergic agents as the experimental model.
GABA and topiramate reduced the percentage of cholesterol ester in lipid-laden HMDMs by down-regulating SR-A, CD36 and LOX-1 expression and up-regulating ABCA1, ABCG1 and SR-BI expression in lipid-laden HMDMs. The production of TNF-α was decreased in GABA-and topiramate-treated lipid-laden HMDMs, and levels of interleukin (IL)-6 did not change. The activation of two signaling pathways, p38MAPK and NF-κB, was repressed by GABA and topiramate in lipid-laden HMDMs.
GABA and topiramate inhibit the formation of human macrophage-derived foam cells and may be a possibility for macrophage targeted therapy of atherosclerotic lesions.
γ-氨基丁酸（GABA）作为主要的抑制性神经递质，作用于GABA受体，在巨噬细胞功能调节中发挥重要作用。本研究检测了GABA和一种GABA受体激动剂对人单核细胞衍生巨噬细胞（HMDMs）中胆固醇代谢相关分子的调节作用。
以暴露于氧化型低密度脂蛋白（ox-LDL）且添加或不添加GABA能药物的HMDMs作为实验模型，进行油红O染色、高效液相色谱法（HPLC）、定量逆转录聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法（Western blot）和电泳迁移率变动分析（EMSA）。
GABA和托吡酯通过下调脂质负载的HMDMs中SR-A、CD36和LOX-1的表达，以及上调ABCA1、ABCG1和SR-BI的表达，降低了脂质负载的HMDMs中胆固醇酯的百分比。在GABA和托吡酯处理的脂质负载的HMDMs中，肿瘤坏死因子-α（TNF-α）的产生减少，白细胞介素（IL）-6水平未改变。GABA和托吡酯抑制了脂质负载的HMDMs中两条信号通路p38丝裂原活化蛋白激酶（p38MAPK）和核因子κB（NF-κB）的激活。
GABA和托吡酯抑制人巨噬细胞源性泡沫细胞的形成，可能为动脉粥样硬化病变的巨噬细胞靶向治疗提供一种可能。
