Analyses of Group III Secreted Phospholipase A(2) Transgenic Mice Reveal Potential Participation of This Enzyme in Plasma Lipoprotein Modification, Macrophage Foam Cell Formation, and Atherosclerosis

作者：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^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283(48): 33483-33497.

DOI：10.1074/jbc.M804628200

Among the many mammalian secreted phospholipase A(2) (sPLA(2)) enzymes, PLA2G3 ( group III secreted phospholipase A2) is unique in that it possesses unusual N- and C-terminal domains and in that its central sPLA(2) domain is homologous to bee venom PLA(2) rather than to other mammalian sPLA(2)s. To elucidate the in vivo actions of this atypical sPLA(2), we generated transgenic (Tg) mice overexpressing human PLA2G3. Despite marked increases in PLA(2) 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 sPLA(2)s 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 A(2) levels. These results collectively suggest a potential functional link between PLA2G3 and atherosclerosis, as has recently been proposed for PLA2G5 and PLA2G10.

• 出版日期2008-11-28
• 单位河北医科大学