Published online before print April 19, 2007, doi: 10.1161/CIRCRESAHA.107.151704
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Submitted on August 3, 2006
Revised on March 30, 2007
Accepted on April 5, 2007
Low Density Lipoprotein Undergoes Oxidation Within Lysosomes in Cells
Yichuan Wen and David S. Leake *
From the Cardiovascular Research Group, Cell and Molecular Biology Research Division, School of Animal and Microbial Sciences, The University of Reading, Berkshire, United Kingdom.
* To whom correspondence should be addressed. E-mail: d.s.leake{at}reading.ac.uk.
The oxidized low density lipoprotein (LDL) hypothesis of atherosclerosis proposes that LDL undergoes oxidation in the interstitial fluid of the arterial wall. We have shown that aggregated (vortexed) nonoxidized LDL was taken up by J774 mouse macrophages and human monocyte-derived macrophages and oxidized intracellularly, as assessed by the microscopic detection of ceroid, an advanced lipid oxidation product. Confocal microscopy showed that the ceroid was located in the lysosomes. To confirm these findings, J774 macrophages were incubated with acetylated LDL, which is internalized rapidly to lysosomes, and then incubated (chase incubation) in the absence of any LDL. The intracellular levels of oxysterols, measured by HPLC, increased during the chase incubation period, showing that LDL must have been oxidized inside the cells. Furthermore, we found that this oxidative modification was inhibited by lipid-soluble antioxidants, an iron chelator taken up by fluid-phase pinocytosis and the lysosomotropic drug chloroquine, which increases the pH of lysosomes. The results indicate that LDL oxidation can occur intracellularly, most probably within lysosomes.
Key words: atherosclerosis • ceroid • lysosome • iron • oxidized low density lipoprotein
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