期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 282, 期 37, 页码 27100-27114出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M701316200
关键词
-
资金
- NCRR NIH HHS [P41 RR000954, P41 RR000954-30, P41 RR 00954] Funding Source: Medline
- NHLBI NIH HHS [P01 HL057278, P01 HL 57278] Funding Source: Medline
- NIDDK NIH HHS [P30 DK056341, P30 DK056341-069003, P60 DK 20579, P30 DK056341-07, R37 DK034388, P60 DK020579, P30 DK056341-06, R37 DK034388-23, R37 DK 34388, P60 DK020579-269005, P30 DK 56341] Funding Source: Medline
- NIGMS NIH HHS [P41 GM103422] Funding Source: Medline
- PHS HHS [R01 69455] Funding Source: Medline
Mouse macrophages undergo ER stress and apoptosis upon free cholesterol loading (FCL). We recently generated iPLA2 beta-null mice, and here we demonstrate that iPLA(2)beta- null macrophages have reduced sensitivity to FCL-induced apoptosis, although they and wild-type (WT) cells exhibit similar increases in the transcriptional regulator CHOP. iPLA(2)beta-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 iPLA(2)beta expression with recombinant adenovirus increases apoptosis toward WT levels. WT and iPLA2 beta-null macrophages incorporate [H-3] arachidonic acid ([H-3] AA]) into glycerophosphocholine lipids equally rapidly and exhibit identical zymosan-induced, cPLA2 beta-catalyzed [H-3] AA release. In contrast, although WT macrophages exhibit robust [H-3] AA release upon FCL, this is attenuated in iPLA(2)beta-null macrophages and increases toward WT levels upon restoring iPLA(2)beta expression. Recent reports indicate that iPLA(2)beta 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 iPLA(2)beta-null cells. Immunoblotting studies indicate that iPLA(2)beta associates with mitochondria in macrophages subjected to ER stress. AA incorporation into glycerophosphocholine lipids is unimpaired in iPLA(2)beta-null macrophages upon electrospray ionization-tandem mass spectrometry analyses, and their complex lipid composition is similar to WT cells. These findings suggest that iPLA(2)beta participates in ER stress-induced macrophage apoptosis caused by FCL or thapsigargin but that deletion of iPLA(2)beta does not impair macrophage arachidonate incorporation or phospholipid composition.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据