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Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice.

Authors
  • Wen, Yichuan1
  • Ahmad, Feroz1
  • Mohri, Zahra2
  • Weinberg, Peter D2
  • Leake, David S3
  • 1 School of Biological Sciences and Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, Berkshire, United Kingdom. , (United Kingdom)
  • 2 Department of Bioengineering, Imperial College London, London, United Kingdom. , (United Kingdom)
  • 3 School of Biological Sciences and Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, Berkshire, United Kingdom. Electronic address: [email protected] , (United Kingdom)
Type
Published Article
Journal
Atherosclerosis
Publication Date
Dec 01, 2019
Volume
291
Pages
9–18
Identifiers
DOI: 10.1016/j.atherosclerosis.2019.09.019
PMID: 31629988
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

We have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice. LDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170 nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19-22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured. Confocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine. These results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

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