Mildly Oxidized LDL Induces Expression of Group IIa Secretory Phospholipase A 2 in Human Monocyte–Derived Macrophages

Abstract

Abstract —Phospholipase A 2 s (PLA 2 s) constitute a family of enzymes that hydrolyze fatty acids of membrane phospholipids, thus initiating the synthesis of proinflammatory mediators. Various PLA 2 s have been detected in human atherosclerotic arteries (advanced lesions); however, only the secretory group of PLA 2 has been shown to specifically hydrolyze low density lipoprotein (LDL)–associated phospholipids and, as such, may play a potential role in atherogenesis. In the present study, we investigated the expression pattern of group IIa, IV, and V PLA 2 s in human macrophages, which are the key cells involved in the onset and perpetuation of atherosclerosis. Immunohistochemical staining by double labeling showed that the secretory nonpancreatic PLA 2 (snpPLA 2 ) is detectable in macrophages in the intima of early atherosclerotic lesions. Reverse transcription–polymerase chain reaction analysis of RNA extracted from human monocytes clearly showed that expression of group IV PLA 2 was enhanced during differentiation into macrophages, with an onset of induction at days 2 to 3 of differentiation. Group V snpPLA 2 was constitutively expressed on differentiation, whereas the detection of group IIa snpPLA 2 was dependent on both differentiation and subsequent stimulation of macrophages. Indeed, the transcription of group IIa snpPLA 2 in macrophages was induced by treatment with minimally modified or mildly oxidized LDL, whereas native, extensively oxidized, or acetylated LDL had no effect. To our knowledge, this is the first report describing induction of group IIa snpPLA 2 expression in human monocyte–derived macrophages. The mRNA levels of cytosolic PLA 2 group IV and snpPLA 2 group V remained unchanged on LDL treatment. Thus, our results show that the expression of distinct PLA 2 enzymes is regulated not only during differentiation of monocytes into macrophages but also on exposure of macrophages to distinct LDL species. Consequently, our results indicate a potential role for both cytosolic and secretory PLA 2 enzymes in inflammation and in macrophage functions related to atherosclerosis, with a specific role for group IIa snpPLA2 in LDL scavenging.