Abstract/Summary

Oxidation of LDL is widely believed to be a key process in the pathogenesis of atherosclerosis. However, LDL oxidation has been shown to be inhibited by interstitial fluid and also large clinical trials have shown no protection by antioxidant. Recent work has shown that LDL can be oxidised by iron within the lysosomes of macrophages. Here, we have explored the possible mechanism by which iron is able to oxidise LDL under lysosomal conditions, and also how lysosomotropic antioxidant, cysteamine is able to prevent it. More recently, it has been shown that human macrophages are able to rapidly phagocytose LDL aggregated by enzymes, such as sphingomyelinase (SMaseLDL) and oxidised it by iron inside lysosomes, which have a pH of about 4.5. Here, the chemical characteristics (lipid hydroperoxides and oxysterols) of SMase-LDL oxidised by inorganic iron at lysosomal pH (4.5) have been determined in vitro and compared to the native LDL. In the lysosomes of macrophages, SMase-LDL increased the intralysosomal lipid peroxidation and ceroid formation which was greatly inhibited by cysteamine. There is good evidence which suggests that lysosomal dysfunction plays an important role in the atherosclerotic plaque development. Here, it is shown that lysosomal oxidation of SMase-LDL in human macrophages can cause lysosomal dysfunction, induce ceroid associated cellular senescence, and increase the expression of inflammatory cytokine like TNF-α. The work here also demonstrates that preventing the lysosomal LDL oxidation, with antioxidants like cysteamine, offers protection against the SMase-LDL induced lysosomal dysfunction