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Minimally-oxidized LDL prevents macrophage apoptosis

Monday, February 20, 2006

Arterioscler Thromb Vasc Biol 2006; Early online edition

Scientists have outlined a mechanism by which minimally oxidized low-density lipoprotein cholesterol (LDL) protects macrophage foam cells in atherosclerotic lesions from apoptosis.

"Although most investigators have reported that OxLDL (generated by exposure to copper) is strongly pro apoptotic, two laboratories have reported that copper-oxidized LDL reduces apoptosis of in vitro cultured cells," explain the researchers.

"The reasons for these differing results are unknown, but could be because of differences in the oxidized moieties present," they reason.

To investigate, the team, led by Agnès Boullier from the University of California, in San Diego, USA, incubated minimally oxidized LDL particles with macrophages in vitro, and studied the effects of these oxidized LDL precursors in mouse models of atherosclerosis.

They report in the journal Arteriosclerosis, Thrombosis, and Vascular Biology that minimally oxidized LDL stopped fully oxidized LDL and free cholesterol from promoting the death of macrophages in vitro and in vivo.

In addition, partially oxidized LDL significantly reduced DNA fragmentation and caspase-3 activity in peritoneal macrophages that had been exposed to fully oxidized LDL.

Minimally oxidized LDL was also shown to activate a pro-survival PI3K/Akt signaling pathway. Indeed, PI3K inhibitors abolished the ability of minimally oxidized LDL to promote macrophage survival.

Of note, lesions from the atherosclerotic mice were found to contain phosphorylated Akt. Combined with their other findings, the authors say their observations are therefore "consistent with the hypothesis that minimally –modified LDL could promote the survival of macrophages in lesions despite numerous pro-apoptotic inducements."

Boullier et al conclude: "A detailed understanding of the oxidative moieties in minimally oxidized LDL responsible for these effects and the signaling pathways leading to the pro-survival impact of minimally oxidized LDL represent important areas for further investigation."