Among the many mammalian secreted phospholipase A 2 (sPLA 2 ) enzymes, PLA2G3 (group III secreted phospholipase A 2 ) 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.

In an effort to elucidate the functions of secreted phospholipase A 2 (sPLA 2 ) enzymes in vivo, we generated transgenic (Tg) mice for group V sPLA 2 (sPLA 2 -V) and group X sPLA 2 (sPLA 2 -X), which act potently on phosphatidylcholine in vitro. We found that sPLA 2 -V Tg mice died in the neonatal period because of respiratory failure. The lungs of sPLA 2 -V Tg mice exhibited atelectasis with thickened alveolar walls and narrow air spaces, accompanied by infiltration of macrophages and only modest changes in eicosanoid levels. This severe pulmonary defect in sPLA 2 -V Tg mice was attributable to marked reduction of the lung surfactant phospholipids, phosphatidylcholine and phosphatidylglycerol. Given that the expression of sPLA 2 -V is greatly elevated in human lungs with severe inflammation, our present results raise the intriguing possibility that this isozyme may contribute to ongoing surfactant hydrolysis often observed in the lungs of patients with respiratory distress syndrome. In contrast, sPLA 2 -X Tg neonates displayed minimal abnormality of the respiratory tract with normal alveolar architecture and surfactant composition. This unexpected result was likely because sPLA 2 -X protein existed as an inactive zymogen in most tissues. The active form of sPLA 2 -X was detected in tissues with inflammatory granulation in sPLA 2 -X Tg mice. These results suggest that sPLA 2 -X mostly remains inactive under physiological conditions and that its proteolytic activation occurs during inflammation or other as yet unidentified circumstances in vivo.