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神经鞘磷脂合成酶2 基因的缺失有抗动脉粥样硬化及抗炎作用

秦睿, 陈明亮, 朱珂, 邓锦波, 石渊渊^*

河南大学医学院，神经生物学研究所，开封475004

摘要

本文以神经鞘磷脂合成酶2 基因敲除(sphingomyelin synthase 2 knockout, SMS2-/-)小鼠为研究对象，旨在探讨神经鞘磷脂(sphingomyelin, SM)代谢与动脉粥样硬化(atherosclerosis, AS)发生之间的关系。雄性3 月龄SMS2-/- 小鼠为实验组，同性别同月龄C57BL/6J (wild-type, WT)小鼠为对照组。用高脂高胆固醇饮食喂养两组小鼠，并给予胆盐以促进AS 斑块的形成。喂养3 个月后解剖观察小鼠主动脉弓，剖开胸腹主动脉进行油红染色以观察AS 斑块发生情况；同时收集小鼠腹腔巨噬细胞，用脂多糖刺激后，提取核蛋白用Western blot 方法检测核因子κB (nuclear factor-κB, NFκB) p65 含量；高脂饮食喂养前后，小鼠断尾取血，酶法测定血清SM 水平，用血脂检测试剂盒检测血脂水平。结果显示，高脂饮食喂养3 个月后，SMS2-/- 小鼠的主动脉弓和胸腹主动脉很少形成AS 斑块，而WT 小鼠则产生了较多AS 斑块；高脂饮食喂养前后， SMS2-/-小鼠血清SM 水平均明显低于WT 小鼠(P<0.05)，而血脂水平并无显著性差异(P>0.05)；高脂饮食喂养后，SMS2-/- 小鼠腹腔巨噬细胞经过脂多糖刺激产生的NFκB p65 含量明显低于WT 小鼠。以上结果提示，SMS2 基因的缺失有抗AS 及抗炎作用，因而可能成为临床治疗的新策略。

关键词： 神经鞘磷脂合成酶2; 神经鞘磷脂; 动脉粥样硬化; 核因子κB

分类号：Q493.5

[Sphingomyelin synthase 2 deficiency decreases atherosclerosis and inhibits inflammation in mice.] [Ariticle in Chinese]

QIN Rui, CHEN Ming-Liang, ZHU Ke, DENG Jin-Bo, SHI Yuan-Yuan^*

Institute of Neurobiology, Medical College of Henan University, Kaifeng 475004, China

Abstract

Plasma sphingomyelin (SM) has been shown to be an independent risk factor for coronary heart disease, and sphingomyelinsynthase 2 (SMS2) contributes to de novo SM biosynthesis and plasma membrane SM levels. The aim of the present study is toevaluate the in vivo role of SMS2 deficiency in serum SM metabolism and atherosclerosis (AS) development. We used male SMS2knockout (SMS2-/-) and C57BL/6J (wild-type, WT) mice as experimental and control groups, respectively. Each group was fed high-fatdiet (1% cholesterol, 20% leaf fat), as well as bile salt for accelerating the atherosclerotic formation. After three months of feeding, themice were killed to observe aortic arches and oil red-stained longitudinal sections of thoracoabdominal aortae. Fasting blood sampleswere taken from the tail vein before and after high-fat diet, and the serum lipid and SM levels were measured by using kits and enzymaticmethod respectively. Western blot was used to analyze the contents of nuclear factor-κB (NFκB) p65 subunit in peritoneal macrophagesstimulated with lipopolysaccharide (LPS) after high-fat diet. The results showed that after high-fat diet, SMS2-/- mice presenteddecreased atherosclerotic lesions in aortic arch and thoracoabdominal aorta compared with WT mice. Regardless of whether high-fat dietwere given or not, SMS2-/- mice showed a significant decrease in serum SM level (P<0.05), but no significant changes in serum lipidlevels, compared with WT mice. The expressions of NFκB p65 were attenuated in macrophages from SMS2-/- mice in response to LPSstimulation compared with those of the WT mice. These results suggest that SMS2 deficiency decreases AS and inhibits inflammationin mice. Thus, SMS2 deficiency may be a potential therapeutic strategy.

Key words: sphingomyelin synthase 2; sphingomyelin; atherosclerosis; nuclear factor-κB

收稿日期：2010-05-05　　录用日期：2010-06-29

通讯作者：石渊渊　　E-mail: syy5161@henu.edu.cn

引用本文：

秦睿, 陈明亮, 朱珂, 邓锦波, 石渊渊. 神经鞘磷脂合成酶2 基因的缺失有抗动脉粥样硬化及抗炎作用[J]. 生理学报 2010; 62 (4): 333-338.

QIN Rui, CHEN Ming-Liang, ZHU Ke, DENG Jin-Bo, SHI Yuan-Yuan. [Sphingomyelin synthase 2 deficiency decreases atherosclerosis and inhibits inflammation in mice.] [Ariticle in Chinese] . Acta Physiol Sin 2010; 62 (4): 333-338 (in Chinese with English abstract).