Hanasaki Kohji, Yamada Katsutoshi, Yamamoto Shigenori, Ishimoto Yoshikazu, Saiga Akihiko, Ono Takashi, Ikeda Minoru, Notoya Mitsuru, Kamitani Shigeki, Arita Hitoshi
Shionogi Research Laboratories, Shionogi and Co., Ltd., Sagisu 5-12-4, Fukushima-ku, Osaka 553-0002, Japan.
J Biol Chem. 2002 Aug 9;277(32):29116-24. doi: 10.1074/jbc.M202867200. Epub 2002 May 20.
The deposition of cholesterol ester within foam cells of the artery wall is fundamental to the pathogenesis of atherosclerosis. Modifications of low density lipoprotein (LDL), such as oxidation, are prerequisite events for the formation of foam cells. We demonstrate here that group X secretory phospholipase A2 (sPLA2-X) may be involved in this process. sPLA2-X was found to induce potent hydrolysis of phosphatidylcholine in LDL leading to the production of large amounts of unsaturated fatty acids and lysophosphatidylcholine (lyso-PC), which contrasted with little, if any, lipolytic modification of LDL by the classic types of group IB and IIA secretory PLA2s. Treatment with sPLA2-X caused an increase in the negative charge of LDL with little modification of apolipoprotein B (apoB) in contrast to the excessive aggregation and fragmentation of apoB in oxidized LDL. The sPLA2-X-modified LDL was efficiently incorporated into macrophages to induce the accumulation of cellular cholesterol ester and the formation of non-membrane-bound lipid droplets in the cytoplasm, whereas the extensive accumulation of multilayered structures was found in the cytoplasm in oxidized LDL-treated macrophages. Immunohistochemical analysis revealed marked expression of sPLA2-X in foam cell lesions in the arterial intima of high fat-fed apolipoprotein E-deficient mice. These findings suggest that modification of LDL by sPLA2-X in the arterial vessels is one of the mechanisms responsible for the generation of atherogenic lipoprotein particles as well as the production of various lipid mediators, including unsaturated fatty acids and lyso-PC.
胆固醇酯在动脉壁泡沫细胞内的沉积是动脉粥样硬化发病机制的基础。低密度脂蛋白（LDL）的修饰，如氧化，是泡沫细胞形成的先决条件。我们在此证明X组分泌型磷脂酶A2（sPLA2-X）可能参与了这一过程。发现sPLA2-X可诱导LDL中磷脂酰胆碱的有效水解，导致大量不饱和脂肪酸和溶血磷脂酰胆碱（溶血PC）的产生，这与经典的IB组和IIA组分泌型磷脂酶A2对LDL的脂解修饰极少形成对比。与氧化LDL中载脂蛋白B（apoB）的过度聚集和片段化相反，用sPLA2-X处理导致LDL负电荷增加，而apoB几乎没有修饰。sPLA2-X修饰的LDL被有效地摄取到巨噬细胞中，诱导细胞胆固醇酯的积累和细胞质中非膜结合脂滴的形成，而在氧化LDL处理的巨噬细胞的细胞质中发现了多层结构的广泛积累。免疫组织化学分析显示，在高脂喂养的载脂蛋白E缺陷小鼠动脉内膜的泡沫细胞病变中，sPLA2-X有明显表达。这些发现表明动脉血管中sPLA2-X对LDL的修饰是产生致动脉粥样硬化脂蛋白颗粒以及包括不饱和脂肪酸和溶血PC在内的各种脂质介质产生的机制之一。
