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Journal of Lipid Research, Vol. 42, 1678-1686, October 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

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

Correspondence to: Michael S. Sinensky, To whom correspondence should be addressed., sinensky{at}etsu.edu (E-mail)

Owing at least in part to oxysterol components that can induce apoptosis, oxidized 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 study, 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 initiated by calcium ion fluxes is the activation of cytosolic phospholipase A₂ (cPLA₂). In the current study, we demonstrate that activation of cPLA₂ does occur in both macrophages and fibroblasts treated with 25-OHC or oxLDL. Activation is evidenced by 25-OHC-induced relocalization of cPLA₂ to the nuclear envelope and arachidonic acid release.

Loss of cPLA₂ activity, either through genetic knockout in mice, or by treatment with a cPLA₂ inhibitor, results in an attenuation of arachidonic acid release as well as of the apoptotic response to oxLDL in peritoneal macrophages or to 25-OHC in cultured fibroblast and macrophage cell lines. — Panini, S. R., L. Yang, A. E. Rusinol, M. S. Sinensky, J. V. Bonventre, and C. C. Leslie. Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized LDL/oxysterol. J. Lipid Res. 2001. 42: 1678–1686.

Supplementary key words: arachidonic acid, calcium, cPLA₂, eicosanoids

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