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, John Turk

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Mouse macrophages undergo ER stress and apoptosis upon free cholesterol loading (FCL). We recently generated iPLA2β-null mice, and here we demonstrate that iPLA2β-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 2β-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 iPLA2β expression with recombinant adenovirus increases apoptosis toward WT levels. WT and iPLA2β-null macrophages incorporate [3H] arachidonic acid ([3H]AA]) into glycerophosphocholine lipids equally rapidly and exhibit identical zymosan-induced, cPLA2β-catalyzed [3H]AA release. In contrast, although WT macrophages exhibit robust [3H]AA release upon FCL, this is attenuated in iPLA 2β-null macrophages and increases toward WT levels upon restoring iPLA2β expression. Recent reports indicate that iPLA2β 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 iPLA2β-null cells. Immunoblotting studies indicate that iPLA2β associates with mitochondria in macrophages subjected to ER stress. AA incorporation into glycerophosphocholine lipids is unimpaired in iPLA2β-null macrophages upon electrospray ionization-tandem mass spectrometry analyses, and their complex lipid composition is similar to WT cells. These findings suggest that iPLA 2β participates in ER stress-induced macrophage apoptosis caused by FCL or thapsigargin but that deletion of iPLA2β does not impair macrophage arachidonate incorporation or phospholipid composition.

Original languageEnglish
Pages (from-to)27100-27114
Number of pages15
JournalJournal of Biological Chemistry
Volume282
Issue number37
DOIs
StatePublished - Sep 14 2007

Fingerprint Dive into the research topics of 'Attenuated free cholesterol loading-induced apoptosis but preserved phospholipid composition of peritoneal macrophages from mice that do not express group VIA phospholipase A<sub>2</sub>'. Together they form a unique fingerprint.

  • Cite this