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Oxidation of low density lipoprotein by ferritin at lysosomal pH and its possible role in atherosclerosis

Ojo, O. O. (2019) Oxidation of low density lipoprotein by ferritin at lysosomal pH and its possible role in atherosclerosis. PhD thesis, University of Reading

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Abstract/Summary

Atherosclerosis leading to coronary heart disease and thrombotic stroke is the leading cause of death worldwide. Oxidised low density protein is considered important by many in this disease. Our laboratory has shown that LDL can be oxidised by iron in the lysosomes of macrophages. Others have demonstrated the presence of oxidised products similar to those formed in vitro by catalytically active iron in advanced atherosclerotic lesions. Ferritin is the body’s main iron storing protein. The role of ferritin in lysosomal LDL oxidation and explored the possible consequences for atherosclerosis were investigated. Ferritin oxidised LDL effectively at lysosomal pH (pH 4.5), much faster than at pH 7.4, as shown by increased formation of oxidised lipids (HPLC and tri-iodide assay) and conjugated dienes (automated spectrophotometry). Ferritin spontaneously released iron at lysosomal pH and iron chelators supressed the oxidation of LDL by ferritin. The degradation of apolipoproteinB-100 and cholesteryl esters of LDL speeded up the oxidation of LDL by ferritin. The lysosomotropic antioxidant cysteamine was shown to be a more appropriate antioxidant to effectively inhibit LDL oxidation by ferritin compared to ascorbate, α-tocopherol and 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) and N, N′- diphenyl 1,4-phenylenediamine (DPPD). The role of ferritin in lysosomal LDL oxidation within macrophages and macrophage function were accessed. Incubation with ferritin and LDL led to increased intracellular lipid, ceroid and lipid peroxidation in lysosomes. Ferritin and LDL treatment increased glycolysis and THP-1 macrophage-like cells became metabolically activated, as shown by a Seahorse analyser. Ferritin-oxidised LDL induced reactive oxygen species formation and apoptosis in macrophages, suggesting LDL oxidation by ferritin in lysosomes might be atherogenic.

Item Type:Thesis (PhD)
Thesis Supervisor:Leake, D.
Thesis/Report Department:School of Biological Sciences
Identification Number/DOI:
Divisions:Faculty of Life Sciences > School of Biological Sciences
ID Code:85424

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