Davis Heart Lung Research Institute, College of Medicine, and Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio 43210-1252, USA.
Life Sci. 2010 Jan 16;86(3-4):95-102. doi: 10.1016/j.lfs.2009.11.009. Epub 2009 Nov 26.
Alpha-lipoic acid (LA) is a commonly used dietary supplement that exerts anti-oxidant and anti-inflammatory effects in vivo and in vitro. We investigated the mechanisms by which LA may confer protection in models of established atherosclerosis.
Watanabe heritable hyperlipidemic (WHHL) rabbits were fed with high cholesterol chow for 6 weeks and then randomized to receive either high cholesterol diet alone or combined with LA (20mg/kg/day) for 12 weeks. Vascular function was analyzed by myography. The effects of LA on T cell migration to chemokine gradients was assessed by Boyden chamber. NF-kappaB activation was determined by measuring translocation and electrophoresis migration shift assay (EMSA).
LA decreased body weight by 15+/-5% without alterations in lipid parameters. Magnetic Resonance Imaging (MRI) analysis demonstrated that LA reduced atherosclerotic plaques in the abdominal aorta, with morphological analysis revealing reduced lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, LA improved vascular reactivity (decreased constriction to angiotensin II and increased relaxation to acetylcholine and insulin), inhibited NF-kappaB activation, and decreased oxidative stress and expression of key adhesion molecules in the vasculature. LA reduced T cell content in atherosclerotic plaque in conjunction with decreasing ICAM and CD62L (l-selectin) expression. These effects were confirmed by demonstration of a direct effect of LA in reducing T cell migration in response to CCL5 and SDF-1 and decreasing T cell adhesion to the endothelium by intra-vital microscopy.
The present findings offer a mechanistic insight into the therapeutic effects of LA on atherosclerosis.
α-硫辛酸（LA）是一种常用的膳食补充剂，在体内和体外具有抗氧化和抗炎作用。我们研究了 LA 可能在已建立的动脉粥样硬化模型中提供保护的机制。
给 Watanabe 遗传性高脂血症（WHHL）兔喂食高胆固醇饲料 6 周，然后随机分为单独高胆固醇饮食组或联合 LA（20mg/kg/天）组，共 12 周。通过肌动描记术分析血管功能。通过 Boyden 室评估 LA 对趋化因子梯度中 T 细胞迁移的影响。通过测定核因子-κB 的易位和电泳迁移率变动分析（EMSA）来确定 NF-κB 的激活。
LA 使体重降低 15+/-5%，而不改变脂质参数。磁共振成像（MRI）分析表明，LA 减少了腹主动脉中的动脉粥样硬化斑块，形态学分析显示脂质和炎症细胞含量减少。与 LA 对动脉粥样硬化的影响一致，LA 改善了血管反应性（降低了血管对血管紧张素 II 的收缩，增加了对乙酰胆碱和胰岛素的舒张），抑制了 NF-κB 的激活，并降低了血管中的氧化应激和关键粘附分子的表达。LA 减少了动脉粥样硬化斑块中的 T 细胞含量，同时降低了 ICAM 和 CD62L（L-选择素）的表达。通过证明 LA 直接作用于减少 T 细胞对 CCL5 和 SDF-1 的迁移以及减少 T 细胞对血管内皮的粘附，通过活体显微镜证实了这些作用。
本研究结果为 LA 治疗动脉粥样硬化的治疗效果提供了机制上的深入了解。
