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J. Biol. Chem., Vol. 282, Issue 37, 27100-27114, September 14, 2007

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Attenuated Free Cholesterol Loading-induced Apoptosis but Preserved Phospholipid Composition of Peritoneal Macrophages from Mice That Do Not Express Group VIA Phospholipase A₂^*

Shunzhong Bao, Yankun Li, Xiaoyong Lei, Mary Wohltmann, Wu Jin, Alan Bohrer, Clay F. Semenkovich, Sasanka Ramanadham, Ira Tabas, and John Turk¹

From the Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110 and the Departments of Medicine and of Anatomy and Cell Biology, Columbia University, New York, New York 10032

Mouse macrophages undergo ER stress and apoptosis upon free cholesterol loading (FCL). We recently generated iPLA₂-null mice, and here we demonstrate that iPLA₂-null macrophages have reduced sensitivity to FCL-induced apoptosis, although they and wild-type (WT) cells exhibit similar increases in the transcriptional regulator CHOP. iPLA₂-null macrophages are also less sensitive to apoptosis induced by the sarcoplasmic reticulum Ca²⁺-ATPase inhibitor thapsigargin and the scavenger receptor A ligand fucoidan, and restoring iPLA₂expression with recombinant adenovirus increases apoptosis toward WT levels. WT and iPLA₂-null macrophages incorporate [³H]arachidonic acid ([³H]AA]) into glycerophosphocholine lipids equally rapidly and exhibit identical zymosan-induced, cPLA₂-catalyzed [³H]AA release. In contrast, although WT macrophages exhibit robust [³H]AA release upon FCL, this is attenuated in iPLA₂-null macrophages and increases toward WT levels upon restoring iPLA₂ expression. Recent reports indicate that iPLA₂ modulates mitochondrial cytochrome c release, and we find that thapsigargin and fucoidan induce mitochondrial phospholipid loss and cytochrome c release into WT macrophage cytosol and that these events are blunted in iPLA₂-null cells. Immunoblotting studies indicate that iPLA₂ associates with mitochondria in macrophages subjected to ER stress. AA incorporation into glycerophosphocholine lipids is unimpaired in iPLA₂-null macrophages upon electrospray ionization-tandem mass spectrometry analyses, and their complex lipid composition is similar to WT cells. These findings suggest that iPLA₂ participates in ER stress-induced macrophage apoptosis caused by FCL or thapsigargin but that deletion of iPLA₂ does not impair macrophage arachidonate incorporation or phospholipid composition.

Received for publication, February 15, 2007 , and in revised form, July 10, 2007.

^* This work was supported by United States Public Health Service Grants R37-DK34388, P01-HL57278, P41-RR00954, P60-DK20579, RO1–69455, and P30-DK56341. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Materials, Experimental Procedures, Results, Figs. 1–5, Tables 1–4, and additional references.

¹ To whom correspondence should be addressed: Washington University School of Medicine, Box 8127, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8190; Fax: 314-362-7641; E-mail: jturk{at}wustl.edu.

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