Sato Hiroyasu, Kato Rina, Isogai Yuki, Saka Go-ichi, Ohtsuki Mitsuhiro, Taketomi Yoshitaka, Yamamoto Kei, Tsutsumi Kae, Yamada Joe, Masuda Seiko, Ishikawa Yukio, Ishii Toshiharu, Kobayashi Tetsuyuki, Ikeda Kazutaka, Taguchi Ryo, Hatakeyama Shinji, Hara Shuntaro, Kudo Ichiro, Itabe Hiroyuki, Murakami Makoto
Biomembrane Signaling Project, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Tokyo 113-8613, Japan.
J Biol Chem. 2008 Nov 28;283(48):33483-97. doi: 10.1074/jbc.M804628200. Epub 2008 Sep 18.
Among the many mammalian secreted phospholipase A2 (sPLA2) enzymes, PLA2G3 (group III secreted phospholipase A2) is unique in that it possesses unusual N- and C-terminal domains and in that its central sPLA2 domain is homologous to bee venom PLA2 rather than to other mammalian sPLA2s. To elucidate the in vivo actions of this atypical sPLA2, we generated transgenic (Tg) mice overexpressing human PLA2G3. Despite marked increases in PLA2 activity and mature 18-kDa PLA2G3 protein in the circulation and tissues, PLA2G3 Tg mice displayed no apparent abnormality up to 9 months of age. However, alterations in plasma lipoproteins were observed in PLA2G3 Tg mice compared with control mice. In vitro incubation of low density (LDL) and high density (HDL) lipoproteins with several sPLA2s showed that phosphatidylcholine was efficiently converted to lysophosphatidylcholine by PLA2G3 as well as by PLA2G5 and PLA2G10, to a lesser extent by PLA2G2F, and only minimally by PLA2G2A and PLA2G2E. PLA2G3-modified LDL, like PLA2G5- or PLA2G10-treated LDL, facilitated the formation of foam cells from macrophages ex vivo. Accumulation of PLA2G3 was detected in the atherosclerotic lesions of humans and apoE-deficient mice. Furthermore, following an atherogenic diet, aortic atherosclerotic lesions were more severe in PLA2G3 Tg mice than in control mice on the apoE-null background, in combination with elevated plasma lysophosphatidylcholine and thromboxane A2 levels. These results collectively suggest a potential functional link between PLA2G3 and atherosclerosis, as has recently been proposed for PLA2G5 and PLA2G10.
在众多哺乳动物分泌型磷脂酶A2（sPLA2）酶中，PLA2G3（III组分泌型磷脂酶A2）独具特色，因为它具有不同寻常的N端和C端结构域，且其中心sPLA2结构域与蜂毒PLA2同源，而非与其他哺乳动物sPLA2同源。为阐明这种非典型sPLA2在体内的作用，我们构建了过表达人PLA2G3的转基因（Tg）小鼠。尽管循环系统和组织中的PLA2活性及成熟的18 kDa PLA2G3蛋白显著增加，但PLA2G3 Tg小鼠在9个月龄前未表现出明显异常。然而，与对照小鼠相比，PLA2G3 Tg小鼠出现了血浆脂蛋白改变。用几种sPLA2对低密度（LDL）和高密度（HDL）脂蛋白进行体外孵育表明，PLA2G3以及PLA2G5和PLA2G10能有效地将磷脂酰胆碱转化为溶血磷脂酰胆碱，PLA2G2F的转化效率较低，而PLA2G2A和PLA2G2E的转化效率极低。PLA2G3修饰的LDL，与PLA2G5或PLA2G10处理的LDL一样，在体外可促进巨噬细胞形成泡沫细胞。在人类和载脂蛋白E缺陷小鼠的动脉粥样硬化病变中检测到了PLA2G3的积累。此外，在致动脉粥样硬化饮食后，在载脂蛋白E缺失背景下，PLA2G3 Tg小鼠的主动脉粥样硬化病变比对照小鼠更严重，同时血浆溶血磷脂酰胆碱和血栓素A2水平升高。这些结果共同表明PLA2G3与动脉粥样硬化之间可能存在功能联系，最近也有人提出PLA2G5和PLA2G10存在这种联系。
