Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized LDL/oxysterol

Owing at least in part to oxysterol components that can induce apoptosis, o xidized LDL (oxLDL) is cytotoxic to mammalian cells with receptors that can internalize it. Vascular cells possess such receptors, and it appears that the apoptotic response of vascular cells to the oxysterols borne by oxLDL is an important part of the atherogenic effects of oxLDL. Thus, an analysis of the signaling pathway of apoptotic induction by oxysterols is of value in understanding the development of atherosclerotic plaque. In a prior stud y, we demonstrated an induction of calcium ion flux into cells treated with 25-hydroxycholesterol (25-OHC) and showed that this response is essential for 25-OHC-induced apoptosis. One possible signal transduction pathway init iated by calcium ion fluxes is the activation of cytosolic phospholipase A( 2) (cPLA(2)). In the current study, we demonstrate that activation of cPLA( 2) does occur in both macrophages and fibroblasts treated with 25-OHC or ox LDL. Activation is evidenced by 25-OHC-induced relocalization of cPLA(2) to the nuclear envelope and arachidonic acid release. jlr Loss of cPLA(2) act ivity, either through genetic knockout in mice, or by treatment with a cPLA (2) inhibitor, results in an attenuation of arachidonic acid release as wel l as of the apoptotic response to oxLDL in peritonea] macrophages or to 25- OHC in cultured fibroblast and macrophage cell lines.