抑制糖脂合成可改善高脂高胆固醇饮食喂养的载脂蛋白 E 基因敲除小鼠和兔的动脉粥样硬化和动脉僵硬。
Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E-/- mice and rabbits fed a high-fat and -cholesterol diet.
机构信息
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
出版信息
Circulation. 2014 Jun 10;129(23):2403-13. doi: 10.1161/CIRCULATIONAHA.113.007559. Epub 2014 Apr 7.
BACKGROUND
Glycosphingolipids, integral components of the cell membrane, have been shown to serve as messengers, transducing growth factor-initiated phenotypes. Here, we have examined whether inhibition of glycosphingolipid synthesis could ameliorate atherosclerosis and arterial stiffness in transgenic mice and rabbits.
METHODS AND RESULTS
Apolipoprotein E(-/-) mice (12 weeks of age; n=6) were fed regular chow or a Western diet (1.25% cholesterol, 2% fat). Mice were fed 5 or 10 mg/kg of an inhibitor of glycosphingolipid synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), solubilized in vehicle (5% Tween-80 in PBS); the placebo group received vehicle only. At 20 and 36 weeks of age, serial echocardiography was performed to measure aortic intima-media thickening. Aortic pulse-wave velocity measured vascular stiffness. Feeding mice a Western diet markedly increased aortic pulse-wave velocity, intima-media thickening, oxidized low-density lipoprotein, Ca(2+) deposits, and glucosylceramide and lactosylceramide synthase activity. These were dose-dependently decreased by feeding D-PDMP. In liver, D-PDMP decreased cholesterol and triglyceride levels by raising the expression of SREBP2, low-density lipoprotein receptor, HMGCo-A reductase, and the cholesterol efflux genes (eg, ABCG5, ABCG8). D-PDMP affected very-low-density lipoprotein catabolism by increasing the gene expression for lipoprotein lipase and very-low-density lipoprotein receptor. Rabbits fed a Western diet for 90 days had extensive atherosclerosis accompanied by a 17.5-fold increase in total cholesterol levels and a 3-fold increase in lactosylceramide levels. This was completely prevented by feeding D-PDMP.
CONCLUSIONS
Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E(-/-) mice and rabbits. Thus, inhibition of glycosphingolipid synthesis may be a novel approach to ameliorate atherosclerosis and arterial stiffness.
背景
糖脂是细胞膜的组成部分，已被证明可以作为信使，传递生长因子引发的表型。在这里，我们研究了抑制糖脂合成是否可以改善载脂蛋白 E 基因敲除（apolipoprotein E(-/-)）小鼠和兔的动脉粥样硬化和动脉僵硬。
方法和结果
12 周龄的载脂蛋白 E 基因敲除（apolipoprotein E(-/-)）小鼠（n=6）喂食普通饲料或西方饮食（1.25%胆固醇，2%脂肪）。给喂食西方饮食的小鼠喂 5 或 10 mg/kg 的糖脂合成抑制剂 D-threo-1-苯甲酰基-2-癸酰氨基-3-吗啉基-1-丙醇（D-PDMP），溶于 5%吐温 80 的 PBS 溶液中；安慰剂组仅接受载体处理。在 20 周和 36 周龄时，进行连续超声心动图检查以测量主动脉内膜中层厚度。主动脉脉搏波速度测量血管僵硬程度。喂食西方饮食的小鼠主动脉脉搏波速度、内膜中层厚度、氧化型低密度脂蛋白、Ca2+沉积、葡萄糖神经酰胺和乳糖神经酰胺合酶活性显著增加。用 D-PDMP 喂养可剂量依赖性地降低这些参数。在肝脏中，D-PDMP 通过增加 SREBP2、低密度脂蛋白受体、HMGCo-A 还原酶和胆固醇流出基因（如 ABCG5、ABCG8）的表达来降低胆固醇和甘油三酯水平。D-PDMP 通过增加脂蛋白脂肪酶和极低密度脂蛋白受体的基因表达来影响极低密度脂蛋白的代谢。喂食西方饮食 90 天的兔出现广泛的动脉粥样硬化，总胆固醇水平增加 17.5 倍，乳糖神经酰胺水平增加 3 倍。用 D-PDMP 喂养可完全预防这种情况。
结论
抑制糖脂合成可改善载脂蛋白 E 基因敲除（apolipoprotein E(-/-)）小鼠和兔的动脉粥样硬化和动脉僵硬。因此，抑制糖脂合成可能是改善动脉粥样硬化和动脉僵硬的一种新方法。
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