Published online before print May 15, 2003, doi: 10.1161/01.ATV.0000077207.49221.06
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© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Lysosomal Enzymes Are Released From Cultured Human Macrophages, Hydrolyze LDL In Vitro, and Are Present Extracellularly in Human Atherosclerotic Lesions
From the Wihuri Research Institute, Helsinki, Finland and Division of Human Genetics (H.D., G.A.G.), Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio.
Correspondence to Petri T. Kovanen, M.D., Ph.D., Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. E-mail Petri.Kovanen{at}wri.fi
Objective— Human atherosclerotic lesions have been shown to contain lipid droplets and vesicles resembling those of in vitro enzymatically modified LDL. However, little is known about the hydrolytic enzymes in the arterial intima that induce fusion of LDL particles and so produce lipid droplets or that induce foam cell formation.
Methods and Results— Human coronary atherosclerotic lesions obtained at surgery and at autopsy were stained for lysosomal acid lipase and cathepsin D. The extracellular areas of macrophage-rich intimal regions of the atherosclerotic lesions stained positively for both cathepsin D and lysosomal acid lipase, whereas normal arteries were negative. When monocyte-derived macrophages were incubated with opsonized zymosan to stimulate the release of lysosomal enzymes from the cells and LDL was incubated with the macrophage-conditioned media, the apolipoprotein B-100, cholesteryl esters, and triacylglycerols of LDL were hydrolyzed. These hydrolytic modifications rendered the LDL particles unstable and induced their fusion. Cultured macrophages and smooth muscle cells took up the hydrolase-modified LDL particles avidly and were transformed into foam cells.
Conclusions— Our in vivo and in vitro results suggest that lysosomal enzymes released from macrophages may induce hydrolytic modification of LDL and foam cell formation in the human arterial intima.
Key Words: macrophage • lysosomal enzymes • LDL • atherosclerosis
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