Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice
Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice
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DOI：
10.1194/jlr.m700261-jlr200
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发表时间：
2008-02-01
影响因子：
6.5
通讯作者：
Garner, Brett
中科院分区：
文献类型：
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作者：
Glaros, Elias N.;Kim, Woojin S.;Garner, Brett
丝氨酸棕榈酰转移酶抑制剂肉豆蔻碱能有效抑制高脂饮食中载脂蛋白E（apoE）基因敲除（-/-）小鼠动脉粥样硬化的发展。这与血浆鞘磷脂（SM）和鞘糖脂水平降低有关。此外，口服肉豆蔻素可降低血浆胆固醇和甘油三酯（TG）水平。在这里，我们的目的是确定肉豆蔻素是否可以抑制已建立的动脉粥样硬化病变的进展（或刺激消退），并检查肝脏和血浆脂质浓度的潜在变化。成年apoE（-/-）小鼠饲喂高脂饲料30天，组织学证实病变形成。重复组小鼠分别饲喂普通饲料和含有肉豆蔻素（0.3 mg/kg/天）的饲料，继续饲喂60 d。肉豆蔻素显著抑制已建立的动脉粥样硬化的进展，当合并病变区域（主动脉窦，弓，腹腔分支点）测量。虽然主要在主动脉远端区域观察到病变进展的抑制，但未发现病变大小的消退。病变进展的抑制与肝脏和血浆SM、胆固醇和TG水平的降低以及肝脏和血浆apoa - 1水平的升高有关，这表明与几种致动脉粥样硬化性脂质相关的途径的调节可能参与其中。
The serine palmitoyl transferase inhibitor myriocin potently suppresses the development of atherosclerosis in apolipoprotein E (apoE) gene knockout (apoE(-/-)) mice fed a high-fat diet. This is associated with reduced plasma sphingomyelin (SM) and glycosphingolipid levels. Furthermore, oral administration of myriocin decreases plasma cholesterol and triglyceride (TG) levels. Here, we aimed to determine whether myriocin could inhibit the progression (or stimulate the regression) of established atherosclerotic lesions and to examine potential changes in hepatic and plasma lipid concentrations. Adult apoE(-/-) mice were fed a high-fat diet for 30 days, and lesion formation was histologically confirmed. Replicate groups of mice were then transferred to either regular chow or chow containing myriocin (0.3 mg/kg/day) and maintained for a further 60 days. Myriocin significantly inhibited the progression of established atherosclerosis when combined lesion areas (aortic sinus, arch, and celiac branch point) were measured. Although the inhibition of lesion progression was observed mainly in the distal regions of the aorta, regression of lesion size was not detected. The inhibition of lesion progression was associated with reductions in hepatic and plasma SM, cholesterol, and TG levels and increased hepatic and plasma apoA-I levels, indicating that the modulation of pathways associated with several classes of atherogenic lipids may be involved.