The oxidation of low density lipoprotein (LDL) was considered to be important in atherogenesis. It is well known that α-tocopherol protects against the oxidation of LDL by cells or copper ions, but α-tocopherol did not protect against cardiovascular disease in large clinical trials, leading some to doubt the importance of oxidised LDL. We have previously shown that LDL is oxidised in the lysosomes of macrophages, due to their acidic pH and presence of redox-active iron, raising the possibility that this is the main site of LDL oxidation, rather than the extracellular space of the arterial intima. We have now enriched LDL with α-tocopherol (by adding α-tocopherol to human plasma followed by the isolation of LDL by ultracentrifugation) and measured its oxidation by monitoring conjugated diene formation in a spectrophotometer set to 37°C and 234 nm. α-Tocopherol-enriched LDL was oxidised much slower by Cu2+ (2, 5 or 20 µM) at pH 7.4, as expected, but was not protected against oxidation by these concentrations of Cu2+, Fe2+ or Fe3+ at pH 4.5 (lysosomal pH). The lack of protection of cardiovascular disease by α-tocopherol is therefore not proof that oxidised LDL is not important in atherosclerosis, if the oxidation of LDL occurs in lysosomes. We therefore need to retest the oxidised LDL hypothesis using antioxidatnts that accumulate in lysosomes and inhibit the oxidation of LDL at acidic pH.
We thank the Iraqi Government for a PhD studentship (HKMA).
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