Lysosomal oxidation of LDL alters lysosomal pH, induces senescence and increases secretion of pro-inflammatory cytokines in human macrophages

Ahmad, F. and Leake, D. S. ORCID: https://orcid.org/0000-0002-1742-6134 (2019) Lysosomal oxidation of LDL alters lysosomal pH, induces senescence and increases secretion of pro-inflammatory cytokines in human macrophages. Journal of Lipid Research, 60. pp. 98-110. ISSN 1539-7262 doi: 10.1194/jlr.M088245

Abstract/Summary

Objective We have shown that aggregated low density lipoproteins (LDL) is internalised by macrophages and oxidised in lysosomes by redox-active iron. We have now investigated if the lysosomal oxidation of LDL impairs lysosomal function and if a lysosomotropic antioxidant can prevent these alterations. Approach and Results LDL aggregated by sphingomyelinase (SMase-LDL) caused increased lysosomal lipid peroxidation in human monocyte-derived macrophages or THP-1 macrophage-like cells, as shown by a fluorescent probe, Foam-LPO. The pH of the lysosomes was increased considerably by lysosomal LDL oxidation as shown by Lysosensor Yellow/Blue and LysoTracker Red. SMase-LDL induced senescence-like properties in the cells as shown by β-galactosidase staining and levels of p53 and p21. Inflammation plays a key role in atherosclerosis. SMase-LDL treatment increased the LPS-induced secretion of TNF-α, IL-6 and MCP-1. The lysosomotropic antioxidant, cysteamine inhibited all of the above changes. Conclusions Targeting lysosomes with antioxidants, such as cysteamine, to prevent the intralysosomal oxidation of LDL might be a novel therapy for atherosclerosis.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/80740
Item Type	Article
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	American Society for Biochemistry and Molecular Biology
Download/View statistics	View download statistics for this item