Objective-Macrophage survival and proliferation is believed to be a contributing factor in the development of early atherosclerotic lesions. Oxidized low density lipoprotein (oxLDL), a key mediator in the pathogenesis of this disease, has been shown to block apoptosis in macrophages deprived of growth factor. In this report, we investigate the mechanism of oxLDL-mediated macrophage survival. Methods and Results-OxLDL, but not native LDL (nLDL), induces an immediate and oscillatory increase in intracellular calcium ([Ca 2ϩ ] i ). We also show that the calcium/calmodulin dependent kinase, eukaryotic elongation factor-2 kinase (eEF2 kinase), is activated in response to oxLDL, an effect that can be blocked by inhibiting calcium mobilization. Furthermore, selective inhibition of eEF2 kinase reverses the prosurvival effect of oxLDL and results in cellular apoptosis. p38 MAP kinase, a negative regulator of eEF2 kinase, is activated on growth factor withdrawal, a response that can be inhibited by oxLDL. Finally, we show that oxLDL, by activating eEF2 kinase, phosphorylates and therefore inhibits eEF2, resulting in an overall decrease in protein synthesis. Key Words: oxidized LDL Ⅲ eEF2 kinase Ⅲ macrophage Ⅲ apoptosis Ⅲ calcium A therosclerosis is a chronic inflammatory disease of the large and medium-sized arteries, and macrophages play a central role in its initiation and progression. 1,2 The accumulation of macrophages in lesions is attributable in part to recruitment of monocytes from the bloodstream, 2 and also to proliferation of macrophages within atherosclerotic lesions. [3][4][5][6] Hence, comprehensive understandings of how macrophage populations in the artery are regulated require knowledge of factors that control the survival and proliferation of macrophages in the arterial intima. Conclusion-TheseOxidized low-density lipoprotein (oxLDL) plays an important role in atherogenesis, in part because of its effects on macrophage recruitment and retention. 7,8 Initial oxidation of LDL and formation of what is often referred to as "minimally modified" LDL stimulates adjacent endothelial and smooth muscle cells to release monocyte chemotactic protein-1 (MCP-1), which facilitates the recruitment of monocytes into the arterial wall. OxLDL itself is chemotactic for monocytes by virtue of its lysophosphatidylcholine content.At high concentrations, oxLDL can be toxic to cultured macrophages and other cells, but at lower concentrations it has clearly been shown to promote macrophage proliferation and inhibit apoptosis. 9 -15 It has been reported that an increase in intracellular calcium ([Ca 2ϩ ] i ) is required for oxLDL to promote macrophage proliferation. 16 However, the downstream mechanisms that are activated by the increased [Ca 2ϩ ] i , have not been fully explored. Eukaryotic elongation factor-2 kinase (eEF2 kinase), also known as calcium/calmodulin dependent kinase III, is a highly conserved protein kinase first identified by Nairn et al. 17 It has been shown to regulate many cellular processes through its ro...